Synthesis of Frondosin B Analogs via Rhodium Catalyzed Carbonyl Ylide Cycloaddition
A dissertation presented to
the faculty of
the College of Arts and Sciences of Ohio University
In partial fulfillment
of the requirements for the degree
Doctor of Philosophy
John H. Bougher
May 2015
© 2015 John H. Bougher. All Rights Reserved.
2
This dissertation titled
Synthesis of Frondosin B Analogs via Rhodium Catalyzed Carbonyl Ylide Cycloaddition
by
JOHN H. BOUGHER
has been approved for
the Department of Chemistry and Biochemistry
and the College of Arts and Sciences by
Mark C. McMills
Associate Professor of Chemistry and Biochemistry
Robert Frank
Dean, College of Arts and Sciences
3
ABSTRACT
BOUGHER, JOHN H., Ph.D., May 2015, Chemistry
Synthesis of Frondosin B Analogs via Rhodium Catalyzed Carbonyl Ylide Cycloaddition
Director of Dissertation: Mark C. McMills
Carbonyl and azomethine ylides can be useful tools in organic synthesis. By
proceeding through a carbonyl or azomethine ylide, rhodium catalyzed cycloaddition
reactions can result in the formation of bridged oxygen or nitrogen heterocycles.
The 8-oxa-6-azabicyclo[3.2.1]octane and 6-oxa-8-azabicyclo[3.2.1]octane cores
are important parts of numerous natural product scaffolds. These scaffolds include
Ribasine, Himalayamine, Ribasidine, and Norribasine. Ribasine is the parent compound
of a class of alkaloids that all have the indanobenzapine core. These alkaloids are
biogenetically related to the isoquinoline alkaloids. The 8,14-epoxy-indano[2,1c][2]benzapine ring may promote biological activity.
Frondosins have shown promising bioactivity profiles. They have been shown to
inhibit binding of interleukin-8 (IL-8) to its receptor as well as protein kinase C. These
natural products have also exhibited HIV-inhibitory activity in anti-HIV assays. We
herein report an approach towards the synthesis of analogs of Frondosin B via a rhodium
catalyzed diazo decomposition reaction to form a carbonyl ylide intermediate, which then
proceeds through a cycloaddition pathway to form the desired synthetic product.
The core structures of these natural products can be obtained via intermolecular or
intramolecular cycloaddition routes mediated by metal catalyzed decomposition of diazo-
4
substituted precursors. These routes make the syntheses of these cores faster and more
efficient.
5
DEDICATION
To my amazing wife, Alexandria
6
ACKNOWLEDGMENTS
I would like to thank my Ph.D advisor, Dr. Mark C. McMills for having me in his
group. I have grown a lot since I started at Ohio University, both as a chemist and as a
person. Thank you for all of your guidance in not only chemistry related issues, but as
well as in my career aspirations. The knowledge and skills you have provided me with
will help me in my career later in life.
I would also like to thank my undergraduate advisor at Allegheny College, Dr. PJ
Persichini for showing me that organic chemistry can be fun and encouraging me to
continue my education.
I am also thankful for all of the current and past members of the McMills’ group.
I would like to thank Dr. Jason Stengel for, even though we only overlapped for a little
time, showing me how real organic chemistry was performed. I would also like to thank
Dr. Oksana Pavlyuk for showing me new laboratory techniques. I would like to thank
Alicia Frantz for some great conversations and company in the lab. I would finally like to
thank all of the undergraduate students who have helped me in my years here.
I would like to thank all of my committee members, Dr. Jeffrey Rack, Dr. Peter
Coschigano, and Dr. Bergmeier for taking the time to be here today and looking through
my dissertation.
I would like to thank the Department of Chemistry and Biochemistry for all that
you have done and all of the help you have given me. Special thanks go out to Carolyn
Khurshid, Marlene Jenkins, Rollie Merriman, Aaron Dillon and many others.
7
I would like to thank my family for always supporting me in all of my endeavors.
I would not have been able to make it this far without your support.
Finally, I would like to thank my wonderful wife, Alexandria Bougher. You have
shown me what true happiness is. I know our long-distance relationship has been difficult
at times, but it is now over. Thanks for all of your love and support throughout this entire
process.
I would like the acknowledge Ohio University and Biomolecular Innovation and
Technology (BMIT) Group for financial support.
8
TABLE OF CONTENTS
Page
Abstract ............................................................................................................................... 3!
Dedication ........................................................................................................................... 5!
Acknowledgments............................................................................................................... 6!
List of Schemes ................................................................................................................. 10!
List of Figures ................................................................................................................... 15
List of Abbreviations ........................................................................................................ 17!
Chapter 1: Introduction ..................................................................................................... 21!
Chapter 2: Background ..................................................................................................... 32
2.1 The reactivity of carbonyl ylides .......................................................................... 32
2.2 Intermolecular carbonyl ylide cycloaddition reactions ......................................... 36
2.3 Intramolecular carbonyl ylide cycloaddition reactions ......................................... 38
2.4 Azomethine Ylides................................................................................................ 40
2.5 Previous Syntheses of Ribasine ............................................................................ 44
2.6 The Frondosins...................................................................................................... 47!
Chapter 3: Syntheses of 8-oxa-6-azabicyclo[3.2.1]octane and 6-oxa-8azabicyclo[3.2.1]octane .................................................................................................... 59
3.1 Background ........................................................................................................... 59
3.2 Model Studies ....................................................................................................... 61
3.3 Phthalic anhydride/cuprate synthesis of 8-oxa-6-azabicyclo[3.2.1]octane........... 67
3.4 Imine synthesis of 8-oxa-6-azabicyclo[3.2.1]octane ............................................ 72
Chapter 4: Syntheses towards Frondosin B analogs ......................................................... 77
4.1 Background ........................................................................................................... 77
4.2 Indene synthesis towards a desoxy-Frondosin B analog ...................................... 78
4.3 Benzofuran synthesis towards Frondosin B .......................................................... 98
4.4 Salicylaldehyde approach towards the benzofuran ester .................................... 104
4.5 Epoxyolefin synthesis ......................................................................................... 105
4.6 Faveline analog synthesis ................................................................................... 110
4.7 Stetter reaction approach towards Frondosin B analog ...................................... 113
Chapter 5: Other Projects ................................................................................................ 119
9
5.1 Albomycin: Synthesis of a C7N amino acid subunit .......................................... 119
5.2 Synthesis of 1-(azetidin-1-yl)-2-diazoethan-1-one ............................................. 125
Experimental ................................................................................................................... 130
References ....................................................................................................................... 160!
Appendix: Selected NMR Spectra .................................................................................. 169!
10
LIST OF SCHEMES
Page
Scheme 1: Catalytic cycle to generate carbonyl ylides .................................................. 34
Scheme 2: Padwa’s tandem cyclization-cycloaddition reaction .................................... 36
Scheme 3: Early Ibata work ........................................................................................... 37
Scheme 4: Padwa’s synthesis of the ribasine core through intermolecular addition of C-N
multiple bonds ................................................................................................................ 38
Scheme 5: McMills’ synthesis of a phorbol analogue ................................................... 39
Scheme 6: Padwa’s synthesis of brevicomins ............................................................... 40
Scheme 7: Padwa’s use of azomethine ylides in synthesis ............................................ 41
Scheme 8: McMills’ use of an azomethine ylide in the formation of a simple precursor to
quinocarcin ..................................................................................................................... 41
Scheme 9: Synthesis of a simple precursor to quinocarcin............................................ 42
Scheme 10: Ollero’s synthesis of Ribasine .................................................................... 45
Scheme 11: Padwa’s synthesis of the ribasine-like core ............................................... 46
Scheme 12: Dominguez approach towards Ribasine ..................................................... 47
Scheme 13: Ovaska approach to Frondosin B ............................................................... 49
Scheme 14: Flynn used a Stille-Heck approach to Frondosin B ................................... 50
Scheme 15: Flynn’s multicomponent coupling approach to Frondosin B ..................... 51
Scheme 16: MacMillan’s enantioselective synthesis of (+)-Frondosin B ..................... 52
Scheme 17: Winne’s concise synthesis of Frondosin B ................................................ 53
Scheme 18: Li’s approach to (+/-) Frondosin B ............................................................ 54
11
Scheme 19: Wright’s approach to Frondosin B ............................................................. 55
Scheme 20: Trauner’s approach using palladium towards Frondosin B. ...................... 57
Scheme 21: Nevado’s approach to Frondosin B using a gold catalyst .......................... 57
Scheme 22: Synthesis for model studies ........................................................................ 63
Scheme 23: Synthetic route to alcohol derivative.......................................................... 64
Scheme 24: Synthesis to bisprotected aldehyde ............................................................ 65
Scheme 25: Synthetic route to oxime 119 ..................................................................... 66
Scheme 26: Synthetic route to diazo compound 121 ..................................................... 67
Scheme 27: Proposed synthesis of the 8-oxa-6-azabicyclo[3.2.1]octane core .............. 69
Scheme 28: Phthalic anhydride approach to the 8-oxa-6-azabicyclo[3.2.1]octane core 70
Scheme 29: Preparation of a Grignard-copper reagent .................................................. 71
Scheme 30: Proposed synthesis of 8-oxa-6-azabicyclo[3.2.1]octane via the imine
pathway .......................................................................................................................... 73
Scheme 31: Attempts to perform a coordinated deprotonation of imine 135 ................ 75
Scheme 32: Retrosynthesis towards a desoxy-Frondosin B analog............................... 78
Scheme 33: Attempt to make indene carboxylic acid .................................................... 79
Scheme 34: Mechanism for carboxylation via oxalyl bromide ..................................... 79
Scheme 35: Synthesis of indene carboxylic acid ........................................................... 80
Scheme 36: Fischer esterification .................................................................................. 80
Scheme 37: Acid chloride approach to ester 151........................................................... 81
Scheme 38: Synthesis of 4-hydroxybutan-2-one ........................................................... 82
Scheme 39: Attempt to make diazocarbonyl 153 .......................................................... 83
12
Scheme 40: Mechanism for the mono-brominated product 159 .................................... 83
Scheme 41: Mechanism of the di-brominated product 160 ........................................... 83
Scheme 42: Attempt to make diazocarbonyl 156 .......................................................... 84
Scheme 43: β-elimination product ................................................................................. 85
Scheme 44: Deprotonation of five-membered ring ....................................................... 85
Scheme 45: Final steps towards the desoxy-Frondosin B analog .................................. 86
Scheme 46: Synthetic route to enolether 168 ................................................................ 86
Scheme 47: β-elimination mechanism ........................................................................... 87
Scheme 48: Proposed synthesis towards the desoxy-Frondosin B analog .................... 87
Scheme 49: Final steps towards the synthesis of the desoxy-Frondosin B analog ........ 88
Scheme 50: Attempts to make enolate ........................................................................... 90
Scheme 51: Attempt to make desoxy-Frondosin B analog beginning with
dimethylcyclohexanone ................................................................................................. 90
Scheme 52: Synthesis of diazobromide ......................................................................... 92
Scheme 53: Synthesis of indene ester ............................................................................ 93
Scheme 54: Synthesis of acid chloride .......................................................................... 94
Scheme 55: DCC coupling to synthesize ester 186 ....................................................... 94
Scheme 56: Ester 186 via a Mitsunobu reaction ............................................................ 95
Scheme 57: First attempt to make diazocarbonyl 190 ................................................... 95
Scheme 58: Second attempt to make diazocarbonyl 190............................................... 96
Scheme 59: Final steps towards the Frondosin B analog .............................................. 97
Scheme 60: Retrosynthesis towards a Frondosin B analog ........................................... 98
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Scheme 61: Synthesis of the benzofuran piece .............................................................. 99
Scheme 62: Willgerodt-Kindler rearrangement mechanism to form thioamide 197 ... 100
Scheme 63: Mechanism for bromination reaction ....................................................... 102
Scheme 64: Mechanism towards amide ....................................................................... 103
Scheme 65: Mechanism towards enamine ................................................................... 104
Scheme 66: Salicylaldehyde approach to the benzofuran ester ................................... 105
Scheme 67: Synthesis of epoxyolefin .......................................................................... 106
Scheme 68: New route to the epoxyolefin ................................................................... 107
Scheme 69: Weinreb amide approach to epoxyolefin ................................................. 109
Scheme 70: Synthesis of TBS-protected alcohol 231 .................................................. 110
Scheme 71: Ring opening of epoxide to provide bromohydrin 233 ............................ 111
Scheme 72: Possible E1cB elimination mechanism ...................................................... 112
Scheme 73: Attempts to couple bromohydrin 232 and aryl bromide 231 ................... 112
Scheme 74: Final steps towards the Faveline analog................................................... 113
Scheme 75: Formation of the benzofuran via a Stetter reaction .................................. 114
Scheme 76: Grignard addition to 242 .......................................................................... 115
Scheme 77: Model reaction of ethynylmagnesium bromide and 242.......................... 115
Scheme 78: Grignard attack, elimination, diazotization, and cycloaddition ............... 116
Scheme 79: Proposed albomycin biosynthetic pathway and functions of alb 7 enzyme120
Scheme 80: Proposed synthesis of the C7N Unit ........................................................ 120
Scheme 81: Aldehyde synthesis of L-arabinose .......................................................... 121
Scheme 82: Aldehyde synthesis from gluconolactone ................................................ 123
14
Scheme 83: Protected lactam formation ...................................................................... 124
Scheme 84: Original synthesis of 1-(azetidin-1-yl)-2-diazoethan-1-one..................... 126
Scheme 85: Coupling reactions ................................................................................... 128
Scheme 86: New route to 1-(azetidin-1-yl)-2-diazoethan-1-one ................................. 129
15
LIST OF FIGURES
Page
Figure 1. Palitoxin and 68 stereogenic centers .............................................................. 22
Figure 2. R and S enantiomers of Thalidomide ............................................................. 25
Figure 3. Diagram showing chemistry as the central science ........................................ 26
Figure 4: Highlighted are the 8-oxa-6-azabicyclo[3.2.1]octane (left) and the 6-oxa-8azabicyclo[3.2.1]octane (right) substructures ................................................................ 27
Figure 5. Natural products containing the 8-oxa-6-azabicyclo[3.2.1]octane substructure28
Figure 6. Natural products containing the 6-oxa-8-azabicyclo[3.2.1]octane substructure29
Figure 7. Structures of Frondosins A-E ......................................................................... 29
Figure 8. General disconnection of 8-oxa-6-azabicyclo[3.2.1]octane and 6-oxa-8azabicyclo[3.2.1]octane ................................................................................................. 31
Figure 9. Carbonyl ylides ............................................................................................... 32
Figure 10. Reactions of carbonyl ylides ........................................................................ 33
Figure 11. Rhodium catalysts used for carbonyl ylide generation................................. 35
Figure 12. Possible mechanism for the formation of the aziridine product ................... 43
Figure 13. Structures of the Frondosins ......................................................................... 48
Figure 14. Natural products containing the 8-oxa-6-azabicyclo[3.2.1]octane core ....... 59
Figure 15. Natural products containing the 6-oxa-8-azabicyclo[3.2.1]octane core ....... 60
Figure 16. Core structures of synthetic targets .............................................................. 60
Figure 17. Retrosynthesis for the 8-oxa-6-azabicyclo[3.2.1]octane core ...................... 60
Figure 18. Retrosynthesis for the 8-oxa-6-azabicyclo[3.2.1]octane core ...................... 61
16
Figure 19. Retrosynthesis for the 6-oxa-8-azabicyclo[3.2.1]octane core ...................... 61
Figure 20. Retrosyntheses for the 8-oxax-6-azabicyclo[3.2.1]octane and the 8-oxa-6azabicyclo[3.2.1]octane cores ........................................................................................ 68
Figure 21. Retrosynthetic scheme for the imine pathway to the 8-oxa-6azabicyclo[3.2.1]octane scaffold ................................................................................... 72
Figure 22. Structures of Frondosins A-E ....................................................................... 77
Figure 23. Structure of the C7N Unit of Albomycin ................................................... 119
Figure 24. 1-(azetidin-1-yl)-2-diazoethan-1-one ......................................................... 125
17
LIST OF ABBREVIATIONS
Alb 7
Albomycin 7 enzyme
BHBr2-SMe2
dibromoborane dimethylsulfide
Boc2O
di-tert-butyl dicarbonate
BTMA-Br3
benzyl trimethylammonium bromide
CSA
camphorsulfonic acid
DBU
1,8-diazobicyclo[5.4.0]undec-7-ene
DCC
N,N-dicyclohexylcarbodiimide
DCE
1,2-dichloroethane
DCM
dichloromethane
DEAD
diethyl azodicarboxylate
DIBAL
diisobutylaluminum hydride
DMAD
dimethyl acetylenedicarboxylate
DMAP
dimethylaminopyridine
DMF
N,N-dimethylformamide
2,2-DMP
2,2-dimethoxypropane
DMP
Dess-Martin periodinane
DMSO
dimethylsulfoxide
Et2O
diethyl ether
HATU
(1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5b]pyridinium 3-oxid hexafluorophosphate)
IBX
2-iodoxybenzoic acid
18
KHMDS
potassium bis(trimethylsilyl)amide
LAH
lithium aluminum hydride
LDA
lithium diisopropyl amide
Li(t-BuO)3AlH
tri-tert-butoxylithium aluminum hydride
mCPBA
meta-chloroperbenzoic acid
Me2TiCl2
dimethyl titanium dichloride
Me2Zn
dimethyl zinc
MeCN
acetonitrile
MeMgBr
methyl magnesium bromide
MeOH
methanol
MOM
methoxymethyl
MOMCl
chloromethyl methyl ether
n-BuLi
n-butyllithium
NaHMDS
sodium bis(trimethylsilyl)amide
NBS
N-bromosuccinimide
NCS
N-chlorosuccinimide
NEt3
triethylamine
NMP
N-methyl-2-pyrrolidone
p-ABSA
para-acetamidobenzenesulfonyl azide
PCC
pyridinium chlorochromate
Pd(PPh3)2Cl2
bis(triphenylphosphine) palladium(II) chloride
Pd(PPh3)4
tetrakistriphenylphosphine palladium
19
PfBr
9-bromo9-phenylfluorene
pTSA
para-toluenesulfonic acid
pTsOH
para-toluenesulfonic acid
RCM
ring closing metathesis
Rh2(acam)4
dirhodium(II) tetraacetamide
Rh2(OAc)4
dirhodium(II) tetraacetate
Rh2(OHex)4
dirhodium(II) tetrahexanoate
Rh2(pfb)4
dirhodium(II)tetrakis(perfluorobutyrate)
rt
room temperature
sec-BuLi
sec-butyllithium
SOCl2
thionyl chloride
T3P
2,4,6-Tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6trioxide
TBAF
tert-butylammonium fluoride
TBDPSCl
tert-butyldiphenylsilyl chloride
TBSCl
tert-butyldimethylsilyl chloride
TBSOTf
tert-butyldimethylsilyl trifluoromethane
t-BuLi
tert-butyllithium
TEA
triethylamine
TFA
trifluoroacetic acid
THF
tetrahydrofuran
TiCl4
titanium(IV) chloride
20
TLC
thin layer chromatography
TMEDA
tetramethylethylenediamine
TMS
trimethylsilane
TMSCl
trimethylsilyl chloride
21
CHAPTER 1: INTRODUCTION
Methodology development has changed significantly over the past half century.
Organic chemists used to focus research efforts on synthesizing natural products just for
the challenge of making structurally complex molecules. With the advancements in
organic chemistry, however, such efforts are now in the minority. Scientists are now
motivated to make molecules and their analogs that have specific molecular function and
biological activity instead.1 To ensure these molecules have the appropriate biological
activity, stereochemistry has become a major focus for chemists. An example of this
achievement is the incredible synthesis of palitoxin, which has 68 defined stereocenters.
(Figure 1)2
22
O
O
OH
O
H 2N
HO
OH
O
OH
HO
HN
OH
HO
O
HN
HO
OH
OH
OH
OH
HO
HO
OH
HO
OH
OH
O
O
OH
OH
OH
HO
OH
OH
OH
OH
HO
HO
OH
O
OH
HO
OH
OH
Figure 1: Palitoxin and 68 stereogenic centers.
Rather than completing a complex natural product synthesis, more recent targets
are molecules that control the active centers of biological systems. These include
molecules that bind to enzymes, receptors, transport and channel proteins, and
ribosomes.1 These are generally what are considered small molecules, with molecular
weights of less than 500 amu.
Molecules that pharmaceutical companies deem feasible are pushed into what are
called clinical trials. Initially there is the so-called “Phase 0” which is the data the
pharmaceutical company collects before selecting a molecule to move forward. Phase 0
23
consists of pharmacodynamics and pharmacokinetics.3 There are typically four phases to
clinical trials. Phase 1 typically consists of a screen for safety. On average, about 40% of
molecules that enter clinical trials fail Phase 1, meaning they were not safe for human
beings.4 If a drug fails a phase, it does not move forward. Phase 2 is used to establish the
efficacy of the drug versus a placebo. This phase is also used to establish if there is a
significant upgrade over similar drugs already on the market.4 Phase 3 is the final
confirmation of safety and efficacy. This phase is typically larger than Phase 2 and uses a
lot more patients.4 The fourth and final phase, Phase 4, is used as sentry studies during
sales. This phase is used to establish additional information, including optimal use, the
benefits and also the risks involved with using the drug.4 Overall, it may take anywhere
from eight to fifteen years for the molecule to make it from the laboratories of the
pharmaceutical company to being approved by the Food & Drug Administration (FDA)
after clinical trials.4 If these molecules make it through clinical trials, they could become
drugs that would help people throughout the world.
Many of the recent discoveries in organic chemistry have not been solitary,
revolutionary discoveries. They have rather been the result of cumulative, small steps,
which have been the result of the increasing number of scientists in the world. Numerous
reactions, including, but not limited to, the aldol,5 Beckmann,6 Claisen,7 Cope,8 DielsAlder,9 Mannich,10 Michael,11 Wittig,12 1,3-dipolar cycloadditions,13 dithiane
methodology,14 ortho metallation,15 pinacol condensation16 and nucleophilic
substitution17 have all been advanced to higher levels, but very few new methods have
24
been produced. Most of the reactions have focused on catalytic modifications,
diasteroselectivity, enantioselectivity, and in-situ multi-step sequences.
With the advent of negative drug interactions from racemic mixtures of synthetic
material, attention has focused away from synthesizing racemic mixtures of compounds
that provide multiple activities. Attention is now focused on the preparation of one
specific enantiomer that can elicit very specific biological activity without causing
unwanted side effects. Biological systems also react differently to enantiomers. One
enantiomer of a drug may cure a disease or relieve symptoms; the opposite antipode
(enantiomer) may be toxic to the person. An example of the problems that can be caused
due to a racemic mixture of a drug was the use of Thalidomide, which was first marketed
in Germany in 1957.18 Thalidomide was a racemic mixture and was used to alleviate pain
and morning sickness in pregnant women. Once the women gave birth though, the babies
were born with deformed and sometimes missing limbs.18 As a result of these birth
defects the structure of Thalidomide had to be examined to determine the cause.
Thalidomide has one chiral center and has an S-enantiomer and an R-enantiomer (Figure
2). The R enantiomer is a fairly safe drug that produces sedative benefits, but the S
enantiomer is the compound that caused the birth defects.18 A dangerous fact about
Thalidomide though, is that even if only the safe R enantiomer of the drug was taken, it
racemizes.18 Due to this devastating outcome of the racemization of Thalidomide, the
Food and Drug Administration (FDA) banned the drug in 1961.18
25
O
O
O
NH
N
O
(R)-thalidomide
O
NH
O
N
O
O
(S)-thalidomide
Figure 2: R and S enantiomers of Thalidomide18
The FDA has restrictions on the registration of racemic drugs due to the
possibility of adverse reactions to specific enantiomers.19 These restrictions have changed
the ways pharmaceutical companies need to operate and the use of these enantiomerically
pure reactions is very beneficial.20 Recent synthetic processes have provided chemists
with straightforward approaches to the synthesis of small enantiomerically pure
compounds through the use of chiral catalytic reactions to produce chirality products
from achiral starting materials. Chemists have also determined methods to provide drugs
on an industrial scale. During this entire process, scientists have gained a better
understanding of the intermolecular interactions involved in all of these reactions
performed on very large scales.21
Chemists have always been fascinated by nature’s complex synthetic
achievements. Nature also provides a significant challenge to make these natural
molecules synthetically. Nature has figured out a way to make these molecules in a chiral
way, so it is the job of chemists to develop reactions that only produce one enantiomer
over another.
Chemistry is a central science; meaning chemistry is everywhere people look.
Chemistry is important for all of the other natural sciences as well. The lines defining
26
each of these natural sciences are beginning to blur between the different sciences and
create interdisciplinary sciences. Organic methodology development is at the heart of
chemistry. Chemistry methods need to be improved upon as well as new methods need to
be developed in order for more complex molecules to be made. Since chemistry is
everywhere people look, organic methodology is at the center of other natural sciences
and interdisciplinary sciences as well (Figure 3).
BIOLOGY
MATHEMATICS
CHEMISTRY
PHYSICS
MATERIALS SCIENCE
PHARMACOLOGY
MEDICINE
Figure 3: Diagram showing chemistry as the central science.
Innovative methodology needs to be developed for the synthesis of complex
heterocyclic compounds, which include natural products like Ribasine and the frondosins.
Syntheses for heterocyclic compounds are important because heterocycles are located in
all areas of chemistry. Heterocycles make up the biggest and most varied group of
organic compounds.22 Heterocycles are mainly found in biologically active sites. They
are synthesized by plants and animals to be used as poisons or coloring agents along with
many other uses.22 An example of how heterocycles are necessary for life is the heme
found in red blood cells.22 A heme is a heterocycle that complexes an iron atom, which
27
allows for the transport of oxygen through our bodies. Chlorophyll A, which is very
similar to heme, is another example of a heterocycle coordinating a magnesium atom to
have plants turn carbon dioxide into breathable oxygen.22 The building blocks of life,
DNA and RNA are also very complex arrangements of a very large amount of
heterocycles.22 Without heterocycles, life would not exist in its present form.
Heterocycles are also found outside of biological systems. Nitrogen-containing
heterocycles tethered to graphene have been used as catalysts for oxygen reduction in
fuel cells.23 Nitrogen containing heterocycles have also been used to generate energetic
salts.24 These energetic salts have the potential to be used as either explosives or
propellants in the future.24
Complex heterocyclic system containing nitrogen include 8-oxa-6azabicyclo[3.2.1]octane and 6-oxa-8-azabicyclo[3.2.1]octane and are found in
compounds such as Ribasine and Solidaline (Figure 4).
O
O
MeO
N
MeO
Me
HO
O
N
O
O
O
CH 3
OMe
OMe
Figure 4: Highlighted are the 8-oxa-6-azabicyclo[3.2.1]octane (left) and the 6-oxa-8azabicyclo[3.2.1]octane (right) substructures.
28
The 8-oxa-6-azabicyclo[3.2.1]octane scaffold is part of numerous natural products
including Ribasine, Himalayamine, and Zoanthamine (Figure 5).
O
O
O
O
O
H
O
H
H
H
O
N
O
O
Ribasine
Me
O
O
N
H
O
O
OH
Me
N
O
Himalayamine
Zoanthamine
Figure 5: Natural Products containing the 8-oxa-6-azabicyclo[3.2.1]octane substructure.
Ribasine is a natural product isolated from the Fumariaceae plant in 1983.25 It is
the parent of a class of alkaloids that all contain the indanobenzepine core. These
alkaloids are biogenetically related to the isoquinoline alkaloids.26 Himalayamine is also
a part of this class of alkaloids. The core structure of these molecules, which is the N,O
five membered ring in each structure, may help promote biological activity.27
The 6-oxa-8-azabicyclo[3.2.1]octane scaffold is also a component of several
natural products including azasugars, β-glucosidase inhibitors, Solidaline, and the
precursor intermediate of deoxygulonojirimycin (Figure 6).
29
HO
HO
HO
O
N
HO
O
azasugar,
B-glucosidase inhibitors
OH
HO
OH
N
H
N
H
NHPh
MeO
OH
OH
O
OH
N
MeO
Me
HO
O
OMe
OMe
precursor
deoxygulonojirimycin
Solidaline
Figure 6: Natural products containing the 6-oxa-8-azabicyclo[3.2.1]octane
substructures.
The frondosins (Figure 7) are a family of oxacyclic heterocyclic sesquiterpenes
collected from a marine sponge displaying promising bioactive profiles.28 The five
structurally related analogs have been shown to inhibit the binding of interleukin-8 (IL-8)
to either its native receptor or protein kinase C. These natural products have also
exhibited HIV-inhibitory activity in HIV assays.28
OH
HO
O
OH
HO
Frondosin A
O
Frondosin B
Frondosin C
Figure 7: Structures of Frondosins A-E
O
OR
O
Frondosin D (R=H)
Frondosin E (R=Me)
30
After examination of the previous syntheses of these molecules, it becomes
evident that it is necessary to investigate new routes to these target molecules. A more
efficient and quicker pathway to the core structure of these molecules is needed. Also,
truncated structures need to be tested to see if biological activity can be obtained using
just the core structure. The focus of our project will be to synthesize Frondosin B analogs
that we hypothesize could have specific biological activity. In order for us to do this, we
will eventually need to make specific molecules with the stereochemistry defined.
Although there are a number of synthetic approaches and novel synthetic solutions to the
frondosin family,29 none of these pathways proceed through a [3+2]-cycloaddition
reaction provided through rhodium catalyzed diazo decomposition using a carbonyl ylide.
Our analysis of the core 8-oxa-6-azabicyclo[3.2.1]octane and 6-oxa-8-aza[3.2.1]octane
structures and the Frondosin family provides that the general scaffold can be synthesized
by using carbonyl as well as azomethine ylides utilizing either intermolecular or
intramolecular [3+2]-cycloaddition reactions provided through rhodium catalyzed diazo
decomposition.
Carbonyl and azomethine ylides are noted for generating 5-, 6-, and 7-membered
heterocycles in an efficient stereocontrolled manner. We will see if this pathway can be
used to generate the core scaffold of Frondosin B.
31
O OR
O
N
O
O
N
R
8-oxa-6-azabicyclo
[3.2.1]octane
6-oxa-8-azabicyclo
[3.2.1]octane
Figure 8: General disconnection of 8-oxa-6-azabicyclo[3.2.1]octane and 6-oxa-8azabicyclo[3.2.1]octane.
32
CHAPTER 2: BACKGROUND
2.1 The reactivity of carbonyl ylides.
Carbonyl ylides have become an indispensible tool in the synthetic chemist’s
arsenals.
These highly reactive dipolar intermediates have been utilized since their
introduction in the 1960’s.30 Ylides can be formed when the lone pair of electrons of a
carbonyl reacts with a carbenoid moiety generated from a diazocarbonyl in the presence
of a dirhodium catalyst. The concomitant loss of nitrogen results in the formation of the
carbonyl ylide, an overall neutral intermediate that contains charged atoms within the
structure. The atomic charges make for a highly reactive intermediate that is able to
undergo a number of synthetically useful transformations.30 These transformations
include [2,3]-rearrangements, C-H/N-H insertion reactions and [3+2]-cycloaddition
reactions. The use of carbonyl ylides can provide a novel pathway toward the formation
of 8-oxa-6-azabicyclo[3.2.1]octane substructures that are difficult to synthesize. The
ylide cycloaddition can occur owing to the dipolar nature of the carbonyl ylide (Figure 9).
R1
O
R2
R3
R4
R1
O
R2
R3
R4
Figure 9: Carbonyl ylides.30
Carbonyl ylides (1) such as those in Figure 10 are in equilibrium with a
corresponding epoxide (2), which is the result of an intramolecular cyclization reaction.
Epoxides such as 2 are sometimes used as precursors for the formation of the carbonyl
33
ylides (Figure 10).30
Substituted ethers (3) can also be formed through concerted
rearrangements and proton transfers.
Carbonyl ylides, once formed, can further
participate in [3+2]-dipolar cycloaddition reactions. Cycloaddition reactions of these
types, shown in Figure 10, may be one of the most efficient and effective reactions
available to the organic chemist because they can form carbon-carbon bonds similar in
efficiency to the Diels-Alder reaction.
In the presence of olefins and alkynes, the
carbonyl ylide serves as the 1,3-dipolar intermediate and will result in many interesting
oxacycles (4).30
R1
O
R2
R3
R1
R4
O
R2
R3
X Y
R4
X
O
R2
1
2
R1
Y
R3
R4
3
R 3 or R 4= Ketone
or Ester
A B
R1
R2
O
A
R3
R4
B
4
Figure 10: Reactions of carbonyl ylides.30
Carbonyl ylides (5) are prepared via a catalytic cycle beginning with a
diazoketone (6). A rhodium catalyst is introduced and the diazoketone goes through a
rhodium catalyzed diazo decomposition to give an electrophilic metal stabilized carbene
34
(7) and loss of nitrogen gas. The metal stabilized carbene is attacked by the nucleophilic
oxygen of the carbonyl, which then proceeds to the carbonyl ylide (Scheme 1).31
Ph
Ph
O
O
N2
O
5
O
6
Rh 2L 4
N2
Ph
Ph
O
O
Rh 2L 4
Rh 2L 4
O
O
7
Scheme 1: Catalytic cycle to generate carbonyl ylides.31
The catalyst used to generate a carbonyl ylide is usually rhodium, or another
organometallic based compound. The bridging ligands can be interchanged based on the
need for selectivity or reactivity (Figure 11). Rhodium is a d7 transition metal and has a
propensity to form rhodium-rhodium metal bonds. These types of catalysts typically have
four ligands in a paddlewheel formation. In Figure 11, dirhodium(II) tetraacetate
(Rh2(OAc)4) gives a good balance of reactivity and selectivity. As reactivity increases,
selectivity decreases and as selectivity increases, reactivity decreases. Figure 11 shows
35
how one can move towards a more reactive catalyst or a more selective catalyst. In Figure
11, dirhodium(II) tetrakis(perfluorobutyrate) (Rh2(pfb)4) is the most reactive because the
perfluorobutyrate bridging ligand is the most electron withdrawing, making the catalyst
overall, more electrophilic, hence more reactive. Dirhodium(II) tetraacetamide
(Rh2(acam)4) is the most selective because the acetamidate bridging ligand is electron
donating, therefore making the catalyst overall less electrophilic and less reactive.32
Figure 11: Rhodium catalysts used for carbonyl ylide generation.32
Carbonyl ylides can be formed through a number of carbonyl derivatives
including ketones, esters and amides as well as several other C=O equivalents. Padwa
and others have developed a number of approaches to the preparation and utilization of
carbonyl ylides in both inter- and intramolecular fashion that uses a tandem cyclizationcycloaddition method (Scheme 2).33 Regitz was one of the first to develop the required
36
diazo group transfer to a carbonyl group. This allows the carbonyl ylide to form when
introduced to a rhodium catalyst.34 Decomposition of diazoketone (8) in the presence of
rhodium acetate resulted in an electrophilic rhodium stabilized metallocarbenoid
intermediate that undergoes attack by the lone pair of electrons of the oxygen of the
carbonyl.
This results in the formation of the carbonyl ylide (9).
In the reaction
provided, a reactive acetylene such as DMAD was added to the carbonyl ylide in order to
trap the 1,3-dipolar intermediate.
This resulted in the formation of the
oxabicyclo[3.2.1]heptane nucleus (10) in good chemical yield.
Ph
Ph
Ph
Rh 2(OAc) 4
O
N2
O
MeO 2C
CO2Me
O
-N2
O
O
8
9
CO2Me
CO2Me
O
10
Scheme 2: Padwa’s tandem cyclization-cycloaddition reaction.30
2.2 Intermolecular carbonyl ylide cycloaddition reactions.
Ibata et al. produced a number of early studies that utilized carbonyl ylides as a
synthetic tool for cycloaddition reactions. Their main focus was a carbonyl ylide derived
from an aromatic ester (11) used for an intermolecular cycloaddition reaction with
various dipolarophiles to provide the formation of cycloadducts (12-14) (Scheme 3).
37
O
MeO
NPh
O
N-phenyl
maleimide
O
H
O
12
OMe
MeO
CO2Me
DMAD
O
O
CO2Me
H
O
11
H
O
13
Benzaldehyde
MeO
O
O
O
Ph
H
14
Scheme 3: Early Ibata work.30, 35
One of the first instances of the addition of a heterocyclic olefinic dipolarophile,
in this case an imine or nitrile to a carbonyl ylide, was described in Padwa’s synthesis of
a straightforward ribasine-like scaffold.36 He first synthesized a model of the simple
ribasine core using a substituted benzylidine imine as the dipolarophile (Scheme 4).
38
H
Ph
N
R
R= SO2Ph, Me
O
Ph
Ph
Ph
O
NH
MeO
16
Rh 2(OAc) 4
N2
CO2Me
15
O
O
Ph
N C CO2Et
CO2Et
O
N
MeO
17
Scheme 4: Padwa’s synthesis of the ribasine core through intermolecular addition of C-N
multiple bonds.36
The cycloadduct of the benzylidine imine and the diazoketone (15) provided
scaffold (16). The reaction was completely regiospecific, but both the endo and exo
products were formed in an 8:1 ratio favoring the endo product.30 Also in Scheme 4,
Padwa used Mander’s reagent (methyl cyanoformate) as the dipolarophile. The addition
of this reagent resulted in the formation of racemic product (17).
2.3 Intramolecular carbonyl ylide cycloaddition reactions.
Intramolecular variants of the carbonyl ylide cycloaddition reactions have been
used in the synthesis of several complex natural products and interesting scaffolds. The
McMills group utilized a tandem ylide formation/dipolar cycloaddition reaction sequence
in the synthesis of several phorbol analogs.37 The use of this methodology can allow for
easier analogue formation with additional functionality easily prepared. McMills utilized
39
the ether bridge formed during the cycloaddition reaction to effect generation of the
quaternary alcohol function of phorbol. The ether opening was effected via generation of
the samarium enolate of the pendant keto-ether (Scheme 5).37
H
Rh2(OHex)4
O
H
O
N2
H
H
O
R
H
O
R
O
18
H
O
R
19
Scheme 5: McMills’ synthesis of a phorbol analogue.37
The yield of this simple tricyclic phorbol analogue (19) was >90%, and was
formed as a single diastereomer. X-ray crystallography also showed the correct relative
stereochemical formation of C8, C9, and C10.
Padwa used an intramolecular carbonyl ylide cycloaddition reaction in
conjunction with an aldehyde as the dipolarophile to synthesize a series of the substituted
brevicomin analogs. The brevicomins are a family of natural products derived from the
Western Pine Beetle and serve as an aggregation pheromone (Scheme 6).38
40
O
N2
O
O
Rh2(OAc)4
H
O
O
H
C2H5
H
C2H5
O
1. (HSCH2)2
Zn(OTf)2
2. Ra[Ni]
20
O
O
H
C2H5
21
Scheme 6: Padwa’s synthesis of brevicomins.38
The oxo-brevicomin derivative (20) was prepared in a 60% yield of a mixture of
exo- and endo- isomers from a diazohexanedione. Dithioketalization of the bicycle
adduct ketone followed by Raney nickel reduction of the resulting dithioketal, provided
the formation of a mixture of the exo- and endo- brevicomins (21) in good chemical
yield. Padwa has used a number of other dipolarophiles in a similar manner to create
other useful natural products.38
2.4 Azomethine Ylides
Azomethine ylides are unique synthetic tools for the formation of carbon-nitrogen
bonds through cycloaddition.
The azomethine ylide formed can be used in the
preparation of various nitrogen-containing rings.39 Despite this subject not receiving the
same attention as carbonyl ylides, it is an additional powerful technique to generate C-N
bonds. Padwa provided an interesting example in 1989 of using an azomethine ylide in
the formation of an interesting azatricyclic analog (25). He begins with diazoketone (22)
in the presence of DMAD and rhodium acetate to afford the carbonyl ylide (23), which
then isomerizes to furnish the azomethine ylide (24). He named this process a dipole
cascade.
After the addition of a dipolarophile and an in situ alkoxy 1,3-shift, he
41
proceeded to get the tricyclic structure (25) (Scheme 7).39 This also showcases some of
the difficulties using this methodology. The stabilized azomethine ylide is the reactive
species rather than the initially formed carbonyl ylide.
O
N
O
N
N2
Hydrogen Shift
O
N
O
O
22
23
O
24
DMAD
O
O
1,3-shift
CO2Me
N
O
O
CO2Me
N
CO2Me
CO2Me
25
Scheme 7: Padwa’s use of azomethine ylides in synthesis.39
Another example of the use of azomethine ylide intermediates from the McMills
group was the formation of a simple precursor to quinocarcin (Scheme 8).40
OCH3
O
OH
O
N
N
H
O
CH 3
CO2H
N
H
N2
N
N
N
R
R
H
Scheme 8: McMills’ use of an azomethine ylide in the formation of a simple precursor to
quinocarcin.40
42
The synthesis (Scheme 9) proceeded from commercially available
tetrahydroisoquinoline acid (26) where the nitrogen had been protected as the BOC
carbamate. The acid was transformed into an aldehyde through a two-step procedure of
reduction with borane, then oxidation with PCC to provide the aldehyde. Oxamination of
the aldehyde resulted in formation of oxime 27. The BOC group was removed, then
diketene was added to provide for the subsequent formation of the α-diazoamide. The
diazo group was introduced using p-ABSA to provide the substrate (28) needed for the
diazo decomposition reaction. 28 was reacted with the methyl acrylate as the
dipolarophile and a catalytic amount of dirhodium tetraacetate to yield the resulting
simple quinocarcin precursor in trace amounts.40 The major product of the reaction was
the aziridine (29). The aziridine was the major reaction product regardless of the reaction
conditions. As an example, the aziridine was generated whether the reaction was
performed at room temperature or at -78°C.40
H
CO2H
1. Boc 2O, NaOH
2. BH 3-THF
3. PCC
H
OCH3
H
NH
26
N
NBoc
1. NH 2OH, pyridine
2. TFA
3. diketene
H
4. pABSA, DBU
N
OCH3
N
N2
27
28
O
O
Rh 2(OAc) 4
methyl acrylate
CO2CH 3
H
H
H
N
OCH3
N
+
O O
29
Scheme 9: Synthesis of a simple precursor to quinocarcin.40
N
N
O O
OCH3
43
The group published a follow-up paper in which they determined that there were
three possible mechanisms likely for the formation of the aziridine over the expected
dipolarophile product (Figure 12).41
N
Ylide
Formation
N
OCH3
COCH 3
O
30
H 3CO
N
N
N
N
N
Direct Carbenoid Formation
COCH 3
Followed by C=N Insertion
N
OCH3
COCH 3
O
O
29
[2+3]
H 3CO
N N
N
N
COCH
3
O
31
Figure 12: Possible mechanisms for the formation of the aziridine product.41
The first mechanistic possibility is the formation of the azomethine ylide 30
which was formed after the addition of catalyst, which can then undergo attack from the
anion to the carbon of the C=N bond and then quenches the positive charge of nitrogen to
give the resulting aziridine 29.41 The second possible mechanism is the initial carbenoid
formation, which then inserts directly into the C=N bond to give the resulting aziridine
29.41 Finally, a mechanism for a noncatalyzed process, which generated a triazole 31
through a [2+3] cycloaddition reaction of azide. This mechanism provides for attack of
44
the diazo group to the oxime to give the resulting triazole 31 which further collapses to
form the aziridine product with concomitant release of nitrogen gas.41
2.5 Previous Syntheses of Ribasine
Syntheses of ribasine have been completed by Ollero42, Padwa36, and
Dominguez43. The Ollero synthesis begins with a chiral aminolactone (32) subsequently
alkylating
with
homopiperonyl
bromide
in
the
presence
of
sodium
bis(trimethylsilyl)amide (NaHMDS) to give the lactone (33) in excellent chemical yield
and diastereomeric purity (Scheme 10).42, 44 This diastereomeric purity is due to the fact
that the phenyl group must be in the axial position, therefore preventing attack on the
same face of the molecule.
45
O
O
Ph
H
O
Br
N
CO2tBu
O
O
Ph
H
NaHMDS
O
O
N
CO2tBu
O
1. MeOH-HCl
2. H 2, Pd(OH) 2
33
32
R
O
O
N
Pf
Br
O
HO 2C
O
2. Et 3N, Pb(NO 3)2
PfBr
3.BTMA-Br3
4.H2CO/p-TsOH
O
H
O
H 2N
1. TMSCl
35
34a R-H
34b R=Br
n-BuLi
O
O
O
PfHN
O
O
O
O
Li
OEt
O
36
O
O
O
NHPf
O
DIBAL
37
O
O
O
O
1. CH2O, MeOH
TFA
O
O
2. NaBH 4
O
O
NH
O
O
O
O
NHPf
OH
38
39
O
O
N
O
40
Scheme 10: Ollero’s synthesis of Ribasine.42, 44
Hydrolysis with HCl of lactone 33 gave amino acid 34. Protection with 9-bromo9-phenylfluorene (PfBr) and aromatic bromination with benzyltrimethylammonium
46
bromide (BTMA-Br3) followed by condensation with formaldehyde gave the resulting
oxazolidinone (35).42
Cyclization of oxazolidinone 35 was accomplished through
butyllithium transmetallation of the bromide to give aminoindanone (36). The lithium
salt of ethyl dimethoxy-o-toluate was then reacted with aminoindanone 36, resulting in
the formation of lactone 37, which was further reduced to the hemiacetal (38) with
DIBAL. Norribasine (39) was prepared by a [3+2] dipolar cycloaddition reaction via
treatment of the hemiacetal 38 with trifluoroacetic acid, forming an oxonium ylide upon
loss of H2O. N-methylation of norribasine gave the desired ribasine (40) final product.42,
44
Padwa et al. has also used an intramolecular carbonyl ylide method to synthesize
the non-nitrogen containing core structure of a compound similar to ribasine. They
prepared α-diazo-β-(o-carbomethoxy)-substituted aryl ketones and used them as model
systems for the method to synthesize the aromatic core (Scheme 11).
O
N2
CO2Et
41
Rh(II)
O
O
O
O
OEt
42
H
EtO
43
Scheme 11: Padwa’s synthesis of the ribasine-like core.45
The six-membered carbonyl ylide dipole (42) was formed from o-allyl-substituted
diazo ketoesters (41) under dirhodium (II) catalysis to provide the desired ribasine core
47
product (43).45
This method provides insight into the synthetic viability of the
intramolecular cyclization-cycloaddition synthesis of the natural product ribasine.
Dominguez provided a racemic synthesis of Ribasine (Scheme 12).43 The
synthesis began with the condensation of (1S,2S)-2-(Methylamino)-1-indanol (44) with
o-bromomethylbenzoyl bromide (45) to provide the bromoalcohol 46. Bromoalcohol 46
was oxidized using PCC to give bromoketone 47. A Wittig reaction was then used to
form the seven-membered ring compound 48. mCPBA was then used to give the racemic
epoxide 49, which was then opened using LAH to give the corresponding alcohols 50.
HO
Br
Br
MeHN
Br
Br
OH
44
PCC
O
N
Et 3N
O
O
45
Ph 3P
PPh 3 O
N
N
O
46
O
47
NaH
HO
LAH
O
N
N
O
50
mCPBA
N
O
49
O
48
Scheme 12: Dominguez approach towards Ribasine.43
2.6 The Frondosins
The Frondosins (Figure 13) are a family of sesquiterpenes collected from a marine
sponge displaying promising bioactive profiles. They have been shown to inhibit the
binding of interleukin-8 (IL-8) to either its native receptor or protein kinase C. These
natural products have also exhibited HIV-inhibitory activity in HIV assays. We report
48
herein an approach to the synthesis of Frondosin B analogs via a rhodium catalyzed
diazo-decomposition reaction, forming a carbonyl ylide intermediate, which proceeds
through a cycloaddition path to form the desired cycloadduct.
OH
HO
O
OH
HO
Frondosin A
O
O
Frondosin B
Frondosin C
OR
O
Frondosin D (R=H)
Frondosin E (R=Me)
Figure 13: Structures of the Frondosins.
The tetracyclic scaffold of the Frondosins is a synthetically challenging target due
to the complex arrangement of the four rings. For Frondosin B alone, there have been
over and handful of completed syntheses. Ovaska utilized a microwave assisted tandem
5-exo cyclization-Claisen rearrangement process to assemble the B-ring structure of
Frondosin B (Scheme 13).29a The key step is the alkyne formed oxo-claisen
rearrangement which proceeds through transition state 51.
49
cyclization/
dehydration
HO
double bond
isomerization
O
OMe
I
+
HO
MeO
α-methylation
H
H
O-demethylation
OH O
OMe O
OH
OMe
5-exo
O
[3,3]
OMe
Ar
O
H
OMe
51
Scheme 13: Ovaska approach to Frondosin B.29a
Flynn used a Stille-Heck reaction sequence to give the Frondosin B structure
(Scheme 14).29b They proceeded through chloro-alkenyl triflate 52 with alkenyl tethered
vinylstannane 53 as the Stille-Heck acceptor. The first step was to couple the two pieces
together at the triflate and stannane positions to give the transition state 54. From this
transition state, the molecule cyclizes to form the seven-membered ring of the Frondosin
B scaffold to give scaffold 55.29b
50
OTf
MeO
Cl
O
O
+
ZnCl2
Cy2NMe
NMP
Me 3Sn
52
Pd(dba) 2
TFP
CuTC
53
O
MeO
Br
O
54
i.) Me 2TiCl2
ii.) H 2, Pd/C
iii.) EtSNa
HO
O
MeO
O
O
55
Scheme 14: Flynn used a Stille-Heck approach to get Frondosin B.29b
Flynn also synthesized (+/-) frondosin B using a multicomponent coupling
approach (Scheme 15).29c This approach began with the bromide 56 and reacting it with
3-methylbutenyne (57) in the presence of a palladium catalyst to give the oalkynylphenolate 58 which then underwent heteroannulative coupling with bromide 59 to
give product 60.29c 60 was then cyclized using a RCM reaction to give the core of
frondosin B (61).29c The ketone was then converted to the gem-dimethyl group using
Me2TiCl2 to give compound 62.29c Selective reduction of the least sterically hindered
olefin gave compound 63 and demethylation of 63 with sodium ethylthiolate gave (+/-)
frondosin B 64.29c
51
O
MeO
Br
MeMgBr
5 mol%
Pd(PPh) 3Cl2
O
59
MeO
Br
MeO
OH
OMgBr
56
O
60
58
57
RCM
O
10 mol%
Pd/C
H2
RO
MeO
MeO
O
R=Me 63
EtSNa
Me 2TiCl2
O
62
O
61
R=H 64
Scheme 15: Flynn’s multicomponent coupling approach to frondosin B.29c
Enantioselective syntheses of Frondosin B have also been done. MacMillan used
a very efficient five-step enantioselective total synthesis of (+)-Frondosin B (Scheme
16).29d The synthesis began with a benzofuran derived boronic acid (65) that was
converted into the trifluoroborate salt (66) using Molander’s procedure.29d The
trifuoroborate salt (66) was then reacted with crotonaldehyde using iminium catalysis to
give aldehyde 67. Allylic alcohol 69 was obtained by reacting 67 with the vinyl lithium
reagent, which was made by the Shapiro reaction of 68.29d The seven-membered ring was
then closed using [Mo(CO)4Br2]2 which proceeded through a π-allyl Friedel Crafts
cyclization to give compound 70, which gave a 2.5:1 preference for the conjugated
olefin.29d (+)-Frondosin B was then completed using boron tribromide in a demethylation
reaction to give 71.29d
52
MeO
O
OH
MeO
B
O
OH
O
65
O
BF 3K
MeO
O
N
66
Ar
O
67
N
H
N
NHTrisyl
68
nBuLi
BBr 3
MeO
HO
O
71
OH
10 mol% [Mo(CO) 4Br 2]2
MeO
O
70
O
69
Scheme 16: MacMillan’s enantioselective synthesis of (+)-Frondosin B.29d
Winne also had a very efficient synthesis for Frondosin B (Scheme 17). They
used a recently developed (4+3) cycloaddition reaction between dienes and furfuryl
alcohol as the key step in the synthesis of Frondosin B29e They began with the fully
functionalized benzofuran alcohol 72 and reacted it with titanium (IV) chloride and 1vinyl-cyclohexene to give (+/-)-O-methyl frondosin B (73). The formal synthesis of
frondosin B was completed using boron tribromide to give the demethylated product
74.29e
53
MeO
OH
O
TiCl4
BBr 3
MeO
72
HO
O
73
O
74
Scheme 17: Winne’s concise synthesis of Frondosin B.29e
The Li group also synthesized (+/-) frondosin B using a [4+3]-cycloaddition
reaction between benzofuran allylic alcohols and dienes (Scheme 18).29f They began with
benzofuran 75 and reduced the ketone to the alcohol using sodium borohydride to give
76.29f 76 was then reacted with diene 77 in a [4+3]-cycloaddition reaction using
camphorsulfonic acid (CSA) to promote the reaction to give compound 78.29f The double
bond was migrated using pTsOH and demethylation was performed using boron
tribromide to give (+/-) frondosin B (79).29f
54
MeO
O
NaBH 4
MeO
OH
O
75
O
77
MeO
CSA, CH 3NO 2
O
78
76
1. TsOH
2. BBr 3
HO
O
79
Scheme 18: Li’s approach to (+/-) frondosin B.29f
The Wright group achieved a synthesis of frondosin B based on a
diastereoselective cycloaddition reaction of tetrabromocyclopropene and an annulated
furan to provide a building block that could be used in the syntheses of both frondosin A
and B (Scheme 19).29g The synthesis began with commercially available ketone 80 and an
asymmetric reduction was done using the (S,S)-Noyori transfer hydrogenation catalyst to
give 81.29g The alcohol was then protected and condensed with tetrabromocyclopropene
to give compound 82 which can be used in both the synethesis of frondosin A and also of
frondosin B.29g 82 was then reacted in a Suzuki reaction to give 83. The annulated
benzofuran 84 was then achieved through ring closure of the alcohol and the remaining
bromide in the presence of stoichiometric copper(I) iodide. Wittig reaction of 84 and
stereoselective hydrogenation of the resulting compound gave 85. 86 was achieved after
deprotection and oxidation of the resulting alcohol. The ether bridge was opened using
55
tributylphosphine, which also allowed for deoxygenation to the olefin to give 87.
Selective hydrogenation using palladium on carbon resulted in compound 88. 88 was
then carried forward to give (+) frondosin B. The gem-dimethyl was put in place using
Me2TiCl2, but also in the process, the methyl group on C8 was inverted as it was later
discovered had precedent in other natural product syntheses.29g Finally, (-) frondosin B
(89) was achieved using sodium ethylthiolate to demethylate and give the resulting
alcohol.
Br
Br
Br
O
1. (S,S) Noyori
O
2. TBSCl
imidazole
O
Br
Br
O
OTBS
81
80
Pd(PPh 3)4
Cs2CO 3
Br
O
MeO
OH
Br
MeO
O
OTBS
OH
82
BF 3K
O
OTBS
83
CuI
MeO
MeO
MeO
MeO
O
1. HF-pyridine
2. DMP
Bu 3P
O
O
2. PtO 2
H2
O
O
O
1. Ph 3PCH 3Br
nBuLi
OTBS
87
O
Pd/C
H2
MeO
O
O
88
1. MeMgBr
CeCl 3
2. Me 2TiCl2
MeO
HO
NaSEt
O
O
OTBS
84
85
86
O
O
89
Scheme 19: Wright’s approach to frondosin B.29g
O
56
Other metals have been used in the synthesis of frondosin B. Trauner used
palladium-catalyzed couplings to nucleophilic heteroarenes to give an enantioselective
synthesis of (-) frondosin B (Scheme 20).29h This synthesis began with the R-configured
alkyne 90 and the known aryl bromide 91 reacting in a Sonogashira coupling reaction to
give compound 92. The alcohol was deprotected and the benzofuran 93 was formed using
potassium carbonate in methanol effected saponification of the acetate followed by
cyclization and iodination. 93 was alkylated with dimethoxylithiocyclohexadiene and
hydrolyzed to give compound 94. NaHMDS and PhNTf2 were used to form the enol
triflate 95. The seven-membered ring was closed using Pd(PPh3)4 and Hunig’s base to
give compound 96. Me2TiCl2 was used to convert the ketone to the gem-dimethyl
compound 97. Demethylation using sodium ethylthiolate gave (-)-frondosin B (98).29h
57
MeO
MeO
MeO
OAc
1. TFA
OAc
Br
91
2. K 2CO 3
3. MsCl
NaI
PMBO
Pd(PPh 3)4
CuI
TEA
90
1. 1,5-dimethoxylithiocyclohexa-1,4-diene
PMBO
O
I
92
93
OMe
MeO
OMe
NaHMDS
O
Pd(PPh 3)4
OTf
O
PhNTf 2
O
2. ion-exchange resin
Me 2CO
O
O
O
94
95
O
96
MeO
HO
1. MeMgBr
NaSEt
O
O
2. Me 2TiCl2
97
98
Scheme 20: Trauner’s approach using palladium towards frondosin B.29h
Nevado used a gold-catalyzed stereocontrolled approach towards frondosin B
(Scheme 21).29i Pivaloate 99 was reacted with 6,6-dimethyl-1-vinyl cyclohexene (100)
with a gold catalyst gave ketone 101, which has reported to be an intermediate on the
way to frondosin B.29i
2.5 mol% [(S)-MeO-DTBM-BIPHEPAu 2]Cl2
5 mol% AgSbF6
NaOMe
OMe OPIv
+
O
OMe
OMe
99
MeO
100
101
Scheme 21: Nevado’s approach to frondosin B using a gold catalyst.29i
58
Frondosin B is a very interesting and complex natural product that has been the
target of numerous synthetic groups. Though it has been made in a variety of different
ways, it still has not been made through a cycloaddition reaction that proceeds through a
diazo decomposition reaction and forms a carbonyl ylide. We are attempting to
synthesize frondosin B through this procedure in the hopes that a more efficient and
quicker route can be discovered, which can possibly increase overall yield by decreasing
the number of synthetic steps. Since we are also focusing on the truncated analogs of
Frondosin B, we will have the truncated structures tested for biological activity to see if
the cores are biologically active just like the parent compound.
59
CHAPTER 3: SYNTHESES OF 8-OXA-6-AZABICYCLO[3.2.1]OCTANE AND 6OXA-8-AZABICYCLO[3.2.1]OCTANE
3.1 Background
The 8-oxa-6-azabicyclo[3.2.1]octane and 6-oxa-8-azabicyclo[3.2.1]octane
substructures are the core framework of several natural products. Some of the natural
products containing the 8-oxa-6-azabicyclo[3.2.1]octane substructure include Ribasine
(102), Himalayamine (103), Ribasidine (104), Norribasine (105) and Zoanthamine (106).
(Figure 14)
O
O
O
H
O
R2
H
O
N
O
O
R1
R3
102 Ribasine, R1 =R2=H, R 3=Me
103 Himalayamine, R1 =OH, R 2=H, R 3=Me
104 Ribasidine, R1 =H, R 2=OH, R 3=Me
105 Norribasine, R1 =R2=R 3=H
O
N
O
106 Zoanthamine
Figure 14: Natural products containing the 8-oxa-6-azabicyclo[3.2.1]octane core.
Natural products that contain the 6-oxa-8-azabicyclo[3.2.1]octane substructure
include a wide variety of compounds such as azasugars, β-glucosidase inhibitors,
deoxygulonojirimycin and Solidaline (Figure 15).26b, 46
60
HO
HO
HO
HO
O
N
O
OH
HO
OH
N
H
N
H
NHPh
MeO
OH
OH
O
OH
N
MeO
Me
HO
O
OMe
OMe
azasugar,
B-glucosidase inhibitors
precursor
deoxygulonojirimycin
Solidaline
Figure 15: Natural products containing the 6-oxa-8-azabicyclo[3.2.1]octane core.26b, 46
The goal of this study was to synthesize truncated skeletons of the natural product
cores, specifically the 8-oxa-6-azabicyclo[3.2.1]octane, 8-oxa-6-azabicyclo[3.2.1]octane
and the 6-oxa-8-azabicyclo[3.2.1]octane core structures (Figure 16).
O
O
O
O OR
O
N
N
R
8-oxa-6-azabicyclo
[3.2.1]octane
N
8-oxa-6-azabicyclo
[3.2.1]octene
O
6-oxa-8-azabicyclo
[3.2.1]octane
Figure 16: Core structures of synthetic targets.
O
O
N2
O
O
N
R
8-oxa-6-azabicyclo
[3.2.1]octane
N
R
O
O
OR
For imine: R=alkyl
For oxime: R=OR
Figure 17: Retrosynthesis for the 8-oxa-6-azabicyclo[3.2.1]octane core.
R
N
61
O
O
N2
O
O
O
O
N
8-oxa-6-azabicyclo
[3.2.1]octene
N
OR
N
Figure 18: Retrosynthesis for the 8-oxa-6-azabicyclo[3.2.1]octene core.
O OR
N
O
O
O
O
N
O
N2
OR
RO
6-oxa-8-azabicyclo
[3.2.1]octane
N
Figure 19: Retrosynthesis for the 6-oxa-8-azabicyclo[3.2.1]octane core.
3.2 Model Studies
To determine if a cycloaddition process would be a viable synthetic pathway to
form structures similar to the 8-oxa-6-azabicyclo[3.2.1]octane, a model study was
developed without an aromatic ring attached as part of the core structure. These reactions
were proposed in order to ensure the cycloaddition reactions could proceed, with more
complex structures targeted for future work. The proposed synthesis is shown in Scheme
22. 2,4-pentandione (107) was used as the starting point for the synthesis of a simple aza
bicycle intermediate. Base deprotonation provides enolate 108, which was reacted with 5bromopentene (109) to give alkylated product (110). The terminal olefin of 110 was then
oxidized via hydroboration to afford alcohol 111.47 The two carbonyl groups of 111 can
be protected as the dithioketals using 1,3-propanedithiol,48 leaving the alcohol available
to be oxidized to the aldehyde via a Swern oxidation49 generating product 112. The
62
aldehyde produced can be differentially protected as the oxo ketal 113 using ethylene
glycol.50 The dithiane can be removed with NCS/silver nitrate conditions51 to provide a
substrate amenable to diazotination with base and p-ABSA giving cyclization precursor
114.52 After deprotection of the aldehyde and formation of oxime 115,53 cyclization with
rhodium acetate affords the final cycloadduct 116.
63
O
O
O
O
O
O
base
1. BH 3, THF
2. H 2O2, NaOH
Br
109
107
O
O
108
HO
110
111
1.
SH SH
2. (COCl) 2
DMSO
3. Et 3N
O
O
S
1. NCS, AgNO3
N2
CH 3 CH 3
S
S
2. p-ABSA, DBU,
MeCN
O
S
OH
HO
S
H
CH 3 CH 3
S
S
S
O
H
O
O
H
H
O
113
114
112
1. H
2. NH 2OR
O
O
N2
Rh 2(OAc) 4
OR
N
O
O
O
N
OR
O
116
N
H
OR
115
Scheme 22: Synthesis for model studies.
The synthesis of the tricycle (Scheme 23) began with 2,4-pentandione (107) and
its deprotonation with sodium ethoxide, then reacting the subsequent enolate with 5bromopentene to give alkylated dione 110.54 After 110 was isolated followed by
64
purification, substrate 110 was reacted with borane and hydrogen peroxide following a
literature procedure47 to give the expected anti-Markovnikov alcohol 111 in moderate
overall yields.
O
O
O
NaOEt
O
BH 3, H 2O2
Br
107
O
O
68%
34%
110
HO
111
Scheme 23: Synthetic route to alcohol derivative.
With alcohol 111 in hand, our first attempt at protecting the carbonyl group with
boron trifluoride diethyletherate and 1,3-propanedithiol48 to provide the bisthioketal
compound 112. Unfortunately, none of the bisthioketal was obtained, only starting
material and the mono-protected dithioketal were obtained. It was concluded that the
bulkiness of the protecting group prohibited the bis-protection. After one ketone was
protected as the dithioketal, the structure was too bulky for another dithioketal to be
formed. After some literature searching, it was found that there are no instances of having
a bis-dithioketal on these types of systems. A dithioketal protecting group works great
when trying to protect a single ketone.48 A better approach would have been to perform
the bis-1,3-dioxolane protection of the ketones. This could be performed using ethylene
glycol and would not have the problem of steric hindrance of a bulky protecting group.55
65
Alcohol 117 would then have to have been oxidized via a Swern oxidation49 to give the
resulting aldehyde 112 (Scheme 24).
O
O
S
SH
SH
S
S
S
S
S
Swern
S
S
BF 3-Et2O
HO
111
HO
117
O
112
Scheme 24: Synthesis to bisprotected aldehyde.
Being unable to prepare the bisthioketal, we chose to prepare the diketoaldehyde
118 without protection, as the newly formed aldehyde should be more reactive than the
ketones (Scheme 25). Swern oxidation49 did indeed prepare the diketoaldehyde in
relatively low yield 38%, and gave a precursor that could potentially provide the requisite
oxime dipolarophile. Diketoaldehyde 118 was then reacted with hydroxylamine
hydrochloride and sodium carbonate to give the resulting methyloxime 119 in very poor
yields.53 It was concluded by 1H NMR, that there was a mixture of oxime products
showing that the aldehyde was not inherently more reactive over the ketone in oxime
formation. In the 1H NMR, there was a visibly smaller aldehyde peak, indicating some
reaction to the oxime occurred, but the aldehyde peak was still visible, meaning other
oxime products generated from reacting with the ketones were formed. Since the reaction
to form the oxime was not very efficient and starting material was scarce, we determined
66
it was not worthwhile to synthesize more starting material, so a different pathway was
chosen.
O
O
HO
111
O
O
O
Swern
NH 2OH-HCl
38%
Na 2CO 3
2%
O
118
MeO
O
O
N
OMe
+
N
119
O
Scheme 25: Synthetic route to oxime 119.
We determined that protection of the aldehyde could provide an additional
pathway toward a similar synthetically viable intermediate (Scheme 26). Aldehyde 118
was subjected to ethylene glycol, p-toluenesulfonic acid and heated to give the resulting
protected aldehyde 120 in low, but reproducible yields.50 With the purified protected
aldehyde available, it was then subjected to Davies conditions for diazocarbonyl
formation with p-acetamidobenzenesulfonyl azide and DBU to give the diazo product
121.52 Crude 1H NMR showed we had a mixture of the desired product as well as the bisdiazo compound. Since this reaction was not as selective as we had hoped, the project
was discontinued in an effort to focus solely on forming the 8-oxa-6azabicyclo[3.2.1]octane cores. While initially the model studies were viewed as
meaningful supplemental data, it became apparent that they provided minimal
information that was of value to the overall project.
67
O
O
O
O
O
O
O
N2
HO
pABSA
OH
DBU
pTsOH
35%
O
118
O
120
O
O
N2
N2
+
O
O
O
O
121
Scheme 26: Synthetic route to diazo compound 121.
3.3 Phthalic anhydride/cuprate synthesis of 8-oxa-6-azabicyclo[3.2.1]octane
The 8-oxa-6-azabicyclo[3.2.1]octane scaffold can be obtained via a rhodium
catalyzed diazo decomposition reaction proceeding through an intramolecular carbonyl
ylide cycloaddition pathway.37 Figure 20 shows our retrosynthetic assessment for both
the 8-oxa-6-azabicyclo[3.2.1]octane and the 8-oxa-6-azabicyclo[3.2.1]octene
cycloaddition products. In both cases, the final step contains a tethered dipolarophile. In
the case of the 8-oxa-6-azabicyclo[3.2.1]octane, an imine or oxime provides a useful
dipolarophile, while in the case of the 8-oxa-6-azabicyclo[3.2.1]octene, a nitrile can be
used as the dipolarophile. One advantage of using the nitrile in the cycloaddition reaction
is that the final product retains an imine in the product, allowing for further derivatization
of the core.
68
O
N2
O
O
O
O
O
N
R
8-oxa-6-azabicyclo
[3.2.1]octane
O
N
R
For imine: R=H, alkyl
For oxime: R=OR
N2
O
8-oxa-6-azabicyclo
[3.2.1]octene
N
OR
O
N
R
O
O
O
N
OR
Figure 20: Retrosyntheses for the 8-oxa-6-azabicyclo[3.2.1]octane and the 8-oxa-6azabicyclo[3.2.1]octene cores.
Our first proposed synthesis towards the 8-oxa-6-azabicyclo[3.2.1]octane and 8oxa-6-azabicyclo[3.2.1]octene core could begin with a cuprate addition to phthalic
anhydride (122),56 with the resulting ketoacid 123 being reduced using lithium tri-tertbutoxyaluminum hydride to give the resulting aldehyde 124 (Scheme 27).57 It was
postulated that the aldehyde would be acetoacylated and diazotized by the addition of
ethyl diazoacetate, 2-iodoxybenzoic acid (IBX), and DBU to give the diazoketoester
125.58 The silicon protecting group could be removed using tert-butylammonium
fluoride59 and the alcohol subsequently oxidized under Swern conditions49 to give
aldehyde 126. The aldehyde was transformed into oxime 127 using methoxyamine
N
69
hydrochloride.53 Once the oxime was in place, rhodium (II) tetraacetate could be used to
give the final cycloaddition product 128.37
O
O
O
O
OR
+
CuLi
OR
Li(t-BuO) 3AlH
OR
OH
O
H
O
123
122
O
124
Ethyl diazoacetate
IBX, DBU, DMSO
OR
N
TBAF
NH 2OR
O
O
OEt
O
N2
OR
O
OEt
O
O
127
N2
126
O
O
Swern
OEt
O
N2
O
125
Rh 2(OAc) 4
RO
N
N
OR
O
O
OEt
O
O
O
OEt
O
128
Scheme 27: Proposed synthesis of the 8-oxa-6-azabicyclo[3.2.1]octane core.
The cuprate necessary for phthalate opening could be made from commercially
available 5-bromopentanol (129), which could be subjected to tert-butyldimethylsilyl
chloride (TBSCl), iodine and sodium thiosulfate to protect the alcohol of 130 in moderate
yield (Scheme 28).60
70
TBSCl
Br
OH
I2
Na 2S2O3
66%
129
Br
OTBS
130
Li
CuI
O
O
O
O
O
OTBS
OTBS
Li(t-BuO) 3AlH
OH
H
O
O
131
Scheme 28: Phthalic Anhydride approach to the 8-oxa-6-azabicyclo[3.2.1]octane core.
The TBS-protected alcohol could then be subjected to lithium metal, copper (I)
iodide and phthalic anhydride to give the resulting carboxylic acid product 131.56 This
type of cuprate is known as a Gilman reagent. These types of organocopper reagents are
typically prepared from either copper (I) bromide or more preferably, copper (I) iodide
and two equivalents of an alkyl lithium or Grignard species. This forms the homocuprate
species known as a Gilman reagent. Theses types of reagents have two of the same alkyl
group attached to the copper, with only one alkyl group being transferred in the reaction.
These reagents are not stable and have to be prepared and used at cold temperatures. The
desired product was not isolated as no reaction product was generated according to crude
H1 NMR. Only starting material remained. It was concluded that the cuprate was not
generated in situ and no coupling of the two derivatives took place. Since the ring
71
opening of the phthalic anhydride could not be performed in a reasonable manner,
another approach was attempted using new pathway.
There are a few other ways to make cuprate reagents. If time had allowed, a
heterocuprate reagent could have been attempted. Since only one alkyl group is usually
transferred in the desired reaction, a non-transferable group can be attached to the copper.
These groups can include an alkyne, Ph2P, R2N, Me3SiCh2, PhS, t-BuO, and 2-thienyl.61
These are not as reactive as Gilman reagents, but are more stable to use. Another way
would have been to employ a cyanocuprate, otherwise known as a Lipshutz reagent.
These have the benefit of being as reactive as Gilman reagents, but also have the stability
of the heterocuprate reagents. Lipshutz reagents can be prepared using copper (I) cyanide
and two equivalents of an alkyllithium species.62 Lastly, a Grignard-copper reagent could
have been used. Since we began with the commercially available 5-bromopentanol and
protected the alcohol, the Grignard could have been made from compound 130. Once the
Grignard (132) was formed, we could have used a catalytic amount of copper (I) iodide to
form the Grignard-copper reagent which would react with phthalic anhydride to give the
desired product 131 (Scheme 29).63
Mg metal
OTBS
Br
130
O
CuI
OR
OR
BrMg
O
OH
132
O
O
131
O
Scheme 29: Preparation of a Grignard-copper reagent.63
72
3.4 Imine synthesis of 8-oxa-6-azabicyclo[3.2.1]octane.
A second approach was attempted to prepare the 8-oxa-6-azabicyclo[3.2.1]octane
core via a different pathway beginning with the azeotropic removal of water from the
reaction of benzo[d][1,3]dioxole-5-carbaldehyde (133) and cyclohexylamine (134)
(Figure 21).64
O
O
H
O
O
N
O
O
N
O MeO OR
OR
O
O
O
OMe
N2
N
OR
O
O
OMe
O
O
+
O
NH 2
Figure 21: Retrosynthetic scheme for the imine pathway to the 8-oxa-6azabicyclo[3.2.1]octane scaffold.
The imine (135) could be deprotonated via a coordinated n-butyllithium
procedure65 followed by a quench with methyl chloroformate and the imine hydrolyzed
with acid to give the resulting aldehyde 136 (Scheme 30). A Grignard made from the
protected alcohol could be used to alkylate the aldehyde to give 137.66 The alcohol could
then be oxidized to the ketone (138) using N-chlorosuccinimide (NCS)67 followed by
TBAF deprotection59 of the alcohol to give 139. The alcohol could be oxidized using
PCC68 and the resulting aldehyde (140) could be transformed into the oxime using
methoxyamine hydrochloride53 to give 141. 141 could then be treated under Davies
conditions52 with p-ABSA and DBU to give the diazo product 142 which could then be
reacted with a rhodium catalyst to perform the final cycloaddition reaction.37
73
O
O
H
azeotropic
N
+
distillation
NH 2
O
O
O
t-BuLi
MeOCOCl
H
O
O
O
134
133
H
OMe
O
136
135
BrMg
OH
O
OMe
O
O
O
OTBS
OTBS NCS
TBAF
OMe
O
OH
O
O
139
OTBS
OMe
O
O
O
O
137
138
PCC
O
O
O
NH 2OR
OMe
O
O
O
140
OMe
O
O
O
OR
N pABSA
O
141
N2
OR
N
OMe
O
O
O
142
Scheme 30: Proposed synthesis of 8-oxa-6-azabicyclo[3.2.1]octane via the imine
pathway.
Imine formation via azeotropic removal of water of benzo[d][1,3]dioxole-5carbaldehyde (133) and cyclohexylamine (134) provided an excellent yield of the imine
(135).64 Deprotonation of the 2-position of the substituted aromatic using n-butyllithium
(n-BuLi), and then quenched with methyl chloroformate followed by hydrolytic
conditions of the pendant imine with aqueous acid, but no acylated products were
found.65 A second attempt was made using the stronger base, sec-BuLi followed by a
quench with methyl chloroformate and then imine hydrolysis with acid, but again, the
desired compound was not formed (Scheme 31).65 An attempt was made using tert-BuLi,
74
then following the same sequence,65 but no product was formed. Some literature reports69
have shown that chelation of the base using TMEDA assisted in the
chelation/deprotonation protocol gave product in cases that did not work without the
TMEDA. TMEDA was added in each of the three bases attempted. The reaction with nBuLi, TMEDA and methyl chloroformate did produce small amounts of the desired
product as evidenced by H1 NMR, but the yields were poor and non-reproducible. It was
also found that the products tended to be difficult to separate. A better way to perform
this experiment would have been to add the base to the reaction, and then quench with
deuterium oxide to see if the deprotonation was happening. If the deprotonation were
happening, then we would know that the imine hydrolysis was the problem. Another
possible solution would be to add carbon dioxide rather than methyl chloroformate and
see if the carboxylic acid were formed. This again would tell us if the deprotonation was
happening as well as nucleophilic attack of the resulting anion. We did get a 14% yield in
one instance with n-BuLi, TMEDA and methyl chloroformate, followed by acid to
hydrolyze the imine. After several other attempts to reproduce this data, nothing could be
obtained. It was concluded via 1H NMR that the problem was probably due to both the
failure coordinately deprotonate the aromatic ring as well as the failure to hydrolyze the
imine with acid.
75
n-BuLi
MeOCOCl
H
sec-BuLi
MeOCOCl
H
t-BuLi
MeOCOCl
H
O
H
azeotropic
+
NH 2
O
O
133
134
distillation
94%
N
O
O
135
O
H
OMe
n-BuLi
TMEDA
MeOCOCl
H
14%
O
O
O
136
sec-Buli
TMEDA
MeOCOCl
H
t-BuLi
TMEDA
MeOCOCl
H
Scheme 31: Attempts to perform a coordinated deprotonation of imine 135.
After several attempts to synthesize the 8-oxa-6-azabicyclo[3.2.1]octane core
scaffold, including a failed phthalic anhydride approach (Scheme 27) and the imine
pathway (Scheme 30), it was concluded that a new natural product should be the focus of
our research. The first approach towards the 8-oxa-6-azabicyclo[3.2.1]octane core
scaffold using phthalic anhydride failed because a suitable cuprate could not be formed in
situ to add into the phthalic anhydride to couple the two derivatives to give the required
intermediate (Scheme 27). The second approach using an imine formation began with
positive results with the formation of the imine proceeding in very good yields. This
approach was hampered though by being unable to perform a coordinated deprotonation
followed by imine hydrolysis. Numerous attempts were made to perform the coordinated
deprotonation, including using various bases ranging from n-BuLi to t-BuLi, as well as
76
including TMEDA as a way to increase the basicity, but nothing helped in the preparation
of the advanced intermediate. Several attempts were made using literature precedent, but
the hydrolyzed imine could not be obtained in reasonable yields to give the requisite
intermediate (Scheme 31).
Model studies were also attempted in an effort to gain an understanding of how
some of the reactions would proceed. Issues were encountered in protecting the diketone
as the bis-dithioketal (Scheme 24). It was concluded that we only obtained the monoprotected dithioketal as well as recovered starting material. These model studies also
were hampered by introduction of the diazo group using Davies conditions (Scheme 26).
1
H NMR showed we had obtained the mono- as well as the bis-diazotized product in no
apparent selectivity. Since there were various complications in the synthetic route of the
model studies, they were abandoned to focus efforts on synthesizing core compounds of
the 8-oxa-6-azabicyclo[3.2.1]octane and 6-oxa-8-azabicyclo[3.2.1]octane substructures.
77
CHAPTER 4: SYNTHESES TOWARDS FRONDOSIN B ANALOGS
4.1 Background
The Frondosins (Figure 22) are a family of sesquiterpenes collected from marine
sponge Dysidea frondosa displaying promising bioactive profiles.29c They have been
shown to be inhibitors of interleukin-8 (IL-8). These types of inhibitors stop the
inflammatory cascade and could possibly be used against autoimmune disorders.29h These
natural products have also exhibited HIV-inhibitory activity in HIV assays.70
OH
HO
O
OH
O
HO
Frondosin A
Frondosin B
Frondosin C
O
OR
O
Frondosin D (R=H)
Frondosin E (R=Me)
Figure 22: Structures of Frondosins A-E
We first chose to synthesize a desoxy-Frondosin B analog, similar to Frondosin C.
The thought process was that we could make the desoxy analog first using indene as a
starting material, then we could make a similar analog beginning with a benzofuran
derivative. Synthesis of a desoxy-Frondosin B structure 143 was determined to be
obtained from 145, which could be synthesized from diazobromide 146 which can be
made in several steps from commercially available indene. The retrosynthesis can be seen
in Scheme 32.
78
O
Cl
HO
O
O
O
O
O
O
O
N2
O
O
143
144
O
145
O
O
N2
O
147
+
Br
146
O
HO
148
Scheme 32: Retrosynthesis towards a desoxy-Frondosin B analog.
4.2 Indene synthesis towards a desoxy-frondosin B analog
Commercially available indene 149 was first subjected to oxalyl chloride in the
hopes that it would yield the carboxylic acid indene 150. (Scheme 33)71 This reaction did
not produce the desired product. The product was supposed to precipitate, but no
precipitate was formed. This same reaction was also attempted using oxalyl bromide, but
this reaction also did not produce the desired product, again failing to produce a
precipitate. Crude 1H NMR only showed starting material for both of these reactions.
This reaction would have to proceed through an acid chloride intermediate and then
quenched with water to form the carboxylic acid. A possible problem with this reaction
was the starting materials were not dry enough and had trace amounts of water in them,
quenching the oxalyl chloride and oxalyl bromide before the acid chloride could be
formed. A better way to make the indene carboxylic acid 150 would be to deprotonate
and use carbon dioxide as the electrophile.
79
O
oxalyl chloride
OH
oxalyl bromide
149
150
Scheme 33: Attempt to make indene carboxylic acid.71
Br
O
H
+
O
O
OH
H 2O
O
O
Br
O
Br
Br
Br
O
O
-CO
Br
Scheme 34: Mechanism for carboxylation via oxalyl bromide.71
Indene (149) was subjected to with n-BuLi and solid carbon dioxide in THF72 to
give the corresponding carboxylic acid 150 in 65% yield and clean enough to carry
forward without purification. (Scheme 35) Carboxylic acid 150 was converted to the acid
chloride via thionyl chloride to give 147 in good yields.73
80
O
n-BuLi, CO2
OH
O
SOCl2
Cl
DCM,
THF, 65%
149
147
150
Scheme 35: Synthesis of indene carboxylic acid.72-73
At this point, we could go 2 possible ways. We could use the acid chloride (147)
and have an alcohol attack it to make the ester (151), or we could make the ester directly
from the carboxylic acid (150) through a Fischer esterification. We thought it would be
more useful to use the carboxylic acid 150 and convert it into the ester and shorten the
sequence. Indene carboxylic acid 150 was heated with 10 mol% sulfuric acid and 4hydroxybutan-2-one to give the ester 151 in 60% yield.74 (Scheme 36)
O
O
150
OH
HO
O
10 mol% H 2SO 4
heat
O
O
151
Scheme 36: Fischer Esterification.74
Acid chloride 147 was reacted with 4-hydroxybutan-2-one and triethylamine to
give the resulting ester 151 in 69% yield.75 (Scheme 37)
81
O
O
Cl
O
HO
O
TEA
147
O
151
Scheme 37: Acid chloride approach to ester 151.75
4-hydroxybutan-2-one (152) could be synthesized starting with commercially
available methyl 3-oxobutanoate (153) and performing a saponification reaction to give
3-oxobutanoic acid (154)76, which could then be protected using ethylene glycol to give
the protected carboxylic acid 155 (Scheme 38).50 The carboxylic acid could then be
reduced to the alcohol by using lithium aluminum hydride to give the resulting protected
alcohol 156.77 The ketone could be deprotected using HCl to give 4-hydroxybutan-2-one.
The saponification reaction of methyl 3-oxobutanoate was attempted and gave good
yields of the resulting carboxylic acid, but this synthesis was abandoned since we found a
supplier that sold the final product 152 at reasonable prices.
82
O
NaOH
O
O
O
HO
O
72%
OH
O
O O
OH
OH
154
153
155
LAH
O
HCl
OH
O
O
OH
152
156
Scheme 38: Synthesis of 4-hydroxybutan-2-one.50, 76-77
At this point in the procedure, there are several synthetic possibilities available to
provide an electrophilic site as part of the substrate. In a first attempt, we could introduce
a bromine atom to begin with and then diazotize α to the carbonyl moiety, or we could
introduce the diazo center prior to placement of the bromine electrophile. For the
introduction of the bromine atom first, ester 151 was subjected to bromine in methanol to
generate the corresponding bromide 157.78 Bromide 157 could then be subjected to
Davies conditions with p-ABSA and DBU to insert the diazo moiety α to the carbonyl
providing the diazo-bromomethyl ketone 158 (Scheme 39).52 This reaction did not
produce the brominated product. Rather, it seemed to give a mixture of inseparable
products possibly including the mono- (159) (Scheme 40)79 and di-brominated (160)
(Scheme 41)80 product of the five-membered ring.
83
O
O
O
O
Br 2, MeOH
p-ABSA
DBU, MeCN
Br
O
157
151
N2
O
Br
O
O
O
158
Scheme 39: Attempt to make diazocarbonyl 153.52, 78
OH
Br
O
Br
O
Br
O
Br
O
O
O
O
OH
Br
O
Br
O
O
O
Br
O
Br
O
HO
O
O
tautomerization
Br
Br
O
O
159
Scheme 40: Mechanism for the mono-brominated product 159.79
O
O
O
O
Br
Br
O
O
Br
O
Br
O
Br
Br
160
Scheme 41: Mechanism for the di-brominated product 160.80
In a second path, we could attempt to introduce the diazo moiety prior to
bromination. (Scheme 42) In that event, ester 151 could be converted into the TMS
O
84
enolether 161 by reacting 151 with lithium diisopropylamide (LDA) followed by trapping
of the enolate with trimethylsilyl chloride (TMSCl).81
O
O
O
LDA, TMSCl
O
O
OTMS
O
161
O
p-ABSA
O
151
O
O
NBS
Br
DBU, MeCN
157
N2
O
Br
158
Scheme 42: Attempt to make diazocarbonyl 156.52, 81-82
Although the reaction provided some product by 1H NMR, the reaction had a
number of side products. Some of these side products include what appeared to be the βelimination product giving methyl vinyl ketone (162) (Scheme 43), other deprotonated
products as the methylene unit on the five-membered ring will have approximately the
same pka as the β protons of the carbonyl (Scheme 44), as well as an abundance of
starting material, while providing only small amounts of the enolether necessary to
continue. If the five-membered ring were deprotonated, any number of side products
could be obtained, including intramolecular attack of the ketone to give an eightmembered ring, as well as intermolecular attack of itself.
85
N
O
O
H
O
O
+
O
162
O
Scheme 43: β-elimination product.
O
O
O
O
Numerous products
O
O
H
N
Scheme 44: Deprotonation of five-membered ring.
Our pathway toward Frondosin B analogs, if the enolether were available, would
be as follows. The TMS enolether 161 would react with N-bromosuccinimide (NBS) to
provide bromide 15782 which was then subjected to Davies conditions with p-ABSA and
DBU to give the diazobromide 158.52
Once diazobromide 158 was in hand, it could be subjected to the enolate of 3,3dimethylcyclohexan-1-one (163) to give the penultimate product diazocarbonyl 164.83
Diazocarbonyl 164 could then be reacted with a rhodium (II) catalyst to give the
cycloaddition product 165.37 The bridged oxygen could be cleaved to give the desoxyFrondosin B analog 166 (Scheme 45).37
86
OTMS
O
O
N2
163
O
Br
O
O
O
O
O
N2
O
158
O
Rh(II) catalyst
HO
O
O
O
O
164
O
SmI2
O
O
O
165
166
Scheme 45: Final steps towards the desoxy-Frondosin B analog.37, 83
With ongoing problems associated with brominating ester 151, a new route was
devised subjecting the acid chloride of indene in a late step of the synthesis.
TBSCl
HO
O
152
imidazole
82%
LDA, TMSCl
TBSO
TBSO
O
167
OTMS
168
Scheme 46: Synthetic route to enolether 168.81, 84
The synthesis began using commercially available 4-hydroxybutan-2-one 152
after protection of the hydroxyl functional group with TBSCl/imidazole.84 This reaction
proceeded smoothly to provide the protected ketone 167, which was further subjected to
LDA and the resulting enolate trapped with TMSCl to give enolether 168 (Scheme 46).81
Unfortunately, this reaction did not proceed as expected and no enolether was isolated. A
possible suggestion as to why no enolether was isolated is that β-elimination occurred
again giving methyl vinyl ketone (162) as the main product (Scheme 47).
87
N
H
TBSO
O
O
162
Scheme 47: β-elimination mechanism.
If we would have isolated enolether 168, we would have brominated using NBS
to provide α-bromomethyl compound 169.82 If bromide 169 were available, it would be
reacted with p-ABSA and DBU to insert the diazo next to the carbonyl to give the
diazocarbonyl 17052, an issue we would struggle with included the regioselectivity of the
diazocarbonyl formation. 3,3-dimethylcyclohexan-1-one could be deprotonated with
sodium hydride to form the kinetic enolate85 and which was then reacted with bromide
170 to give compound 171, but would also result in a mixture of products. (Scheme 48)
O
NBS
TBSO
TBSO
Br
OTMS
168
p-ABSA
DBU
Br
O
170
O
TBSO
TBSO
O
169
N2
N2
NaH
O
171
Scheme 48: Proposed synthesis towards the desoxy Frondosin B analog.52, 82, 85
One alternative to this strategy would be to make the sterically encumbered
enolate through a cuprate addition of a methyl group ((CH3)2CuLi addition to 3-methyl
cyclohexenone) and then trapping with TMS- or TBS-chloride.83 The TBS-protected
88
alcohol 171 could be deprotected using TBAF to restore the compound to alcohol 172.59
Alcohol 172 would finally be subjected to a base to form the alkoxide and then react with
the acid chloride of indene (147) to give cyclization precursor 173 which could then be
subjected to rhodium catalysis for ylide formation followed by cycloaddition.37 (Scheme
49)
O
N2
N2
O
TBSO
TBAF
O
171
Cl
O
HO
147
O
O
O
O
O
HO
N2
O
172
O
O
173
Scheme 49: Final steps towards the synthesis of the desoxy-Frondosin B analog.37, 59, 83
Since the original attempt to make the enolate using LDA and TMSCl did not
work, other attempts were made (Scheme 50). The synthesis of the enolate was attempted
using various bases including potassium bis(trimethylsilyl)amide (KHMDS) and LDA as
well as various trapping agents including TBSCl and acetic anhydride, but no
combination provided the trapped enolate. It was determined that a suitable amount of
LDA was not formed in situ and the resulting trapped enolate was not formed in an
isolable yield. Crude 1H NMR of the various reactions did show a very small amount of
trapped enolate being formed, but nothing could be isolated. The final attempt was to trap
the enolate and also brominate in one pot. KHMDS was used to deprotonate to form the
enolate, TMSCl was used to trap the enolate and bromine was added to form the bromide
89
from the trapped enolate. Crude 1H NMR appeared to show the formation of the
brominated product as the methyl peak shifted from 2.12 ppm downfield to 5.2 ppm due
to the introduction of the bromine atom. The reaction did not appear to run to completion
though, as only a small amount of the brominated product formed and not in enough yield
to isolate. In all of these instances using strong bases LDA and KHMDS, β-elimination
could be the reason no trapped enolate could be isolated. If β-elimination were to occur,
methyl vinyl ketone would be the resulting product in the same manner that is shown in
Scheme 47.
TBSO
OTBS
TBSO
Br
KHMDS
TBSCl
KHMDS
TMSCl
Br 2
TBSO
OTBS
O
LDA, TBSCl
TBSO
O
LDA,
acetic anhydride
LDA, TMSCl
TBSO
TBSO
OTMS
O
O
Scheme 50: Attempts to make enolate.86
90
Another synthesis was devised using the more hindered enolether provided by
conjugate addition to 3-methylcyclohexenone as the starting point. (Scheme 51)
O
O
Br
OEt
N2
178
O
OTBS
N2
TiCl4
OEt
O
O
CuI
MeMgBr
TBSCl
CuI, LiCl
MeMgBr
TMSCl
O
OTMS
TBAF
177
179
O
O
Br
174
175
OEt
N2
178
OH
176
Scheme 51: Attempt to make desoxy-Frondosin B analog beginning with
dimethylcyclohexanone.59, 83, 87
The synthesis began using commercially available 3-methylcyclohex-2-en-1-one
174 to generate a highly substituted nucleophile. The nucleophile is prepared through a
Michael addition to the enone to generate the gem dimethyl group, while providing the
nucleophilic silyl enolether 175.83 Methyl magnesium bromide was first added to
copper(I) iodide and lithium chloride to form the cuprate. 3-methylcyclohex-2-en-1-one
was then added to the cuprate with TMSCl to yield the trapped enolate.83 Unfortunately,
this did not occur. Our analysis of the 1H NMR data concluded that the cuprate did not
form in situ, therefore, the Michael addition could not occur. A small singlet was
observed at 1.18 ppm indicating the methyl magnesium bromide added in a 1,2 fashion to
91
the carbonyl of 3-methylcyclohex-2-en-1-one to give 1,3-dimethylcyclohex-2-en-1-ol
(176) rather than the desired product.
The reaction was attempted again, with TBSCl used as the trapping agent.
Unfortunately, this reaction also did not proceed as anticipated to provide the silyl
enolether 177. Again, 1H NMR showed a small peak indicating a 1,2-addition of methyl
magnesium bromide to the carbonyl rather than a 1,4-addition. This indicated that the
cuprate again, did not form in situ. The lack of formation of the cuprate in situ could be
due to impure copper (I) iodide or traces of water in the copper (I) iodide. If there is
water in the copper (I) iodide, the cuprate will not form. A possible solution to this
problem includes using methyl lithium as a nucleophile to perform the Michael addition
rather than the cuprate. Other possible solutions could be to use copper (I) bromide,
rather than copper (I) iodide to form the Gilman reagent. A heterocuprate could be
formed, using a non-transferable group along with the methyl that would need to be
transferred.61 Finally, a Lipshutz copper reagent could be used. This is a cyanocuprate
that has the reactivity of a Gilman reagent, but the stability of a heterocuprate.62 If the
reaction were successful, addition of the diazo alkyl chain 178 would provide a
cyclization precursor 179 to generate the desoxy-Frondosin. Titanium (IV) chloride could
be used as a Lewis acid to promote coupling of the diazo alkyl chain 178 to the enolether
177.87 The final product could also be obtained by a one-pot deprotection of the enolether
177 using tert-butylammonium fluoride (TBAF) and reacting the enolate with the diazo
alkyl chain 178 to provide the final desired product (179).59
92
O
Br
HgO
180
+
O
H
O
N2
181
O
Et 2O
50%
O
Hg
EtO
N2
N2
Br
183
OEt
O
OEt
69%
182
O
Br
N2
178
Scheme 52: Synthesis of diazobromide.88
The substituted enolether 177 needed to react with diazobromide 178. The
synthesis of diazobromide 178 began with yellow mercuric oxide (180) being added to
ethyl diazoacetate 181 to give the resulting mercury diazoacetate 182 as a yellow solid
that precipitated out of solution in 50% yield that was very reproducible.88 Mercuryl
diazoacetate 182 was then reacted with bromoacetyl bromide (183) to give the final diazo
bromide compound 178 in a 69% yield that was also very reproducible and easily isolable
(Scheme 52).88
At this time, upon reanalyzing the project, it became apparent that this pathway
would not yield the final product we were looking to achieve. In fact, the current pathway
resulted in the electronics of the cycloaddition being reversed. Hence, we had to find a
new synthetic pathway, which would provide the Frondosin B analog. A new synthesis
was devised where we could change the electronics and allow the cycloaddition to
proceed in the necessary fashion.
In a similar reaction sequence, the synthesis begins with commercially available
indene (149). Indene reacts with n-BuLi followed by the addition of solid carbon dioxide
“dry ice” to provide the carboxylic acid 150.72 Rather than form the acid chloride as was
part of the previous sequence, we chose to reduce the carboxylic acid using lithium
93
aluminum hydride to form alcohol 184.77 Alcohol 184 could be further reacted with acid
chloride 185 to provide ester 186. (Scheme 53)
O
O O
OH
n-BuLi, CO2
149
THF
150
OH
O
Cl
LAH
185
THF
NEt 3, DCM
184
O
O O
O
186
Scheme 53: Synthesis of indene ester.72, 77
Acid chloride 185 could be synthesized from commercially available 4hydroxybutan-2-one (152) and the ketone could be protected using ethylene glycol to
give protected ketone 187.50 The primary alcohol could be oxidized to the carboxylic acid
using Jones reagent to provide 188.89 Finally, the carboxylic acid moiety could be
converted to acid chloride 185 using thionyl chloride (Scheme 54).73 The ethylene glycol
protection and Jones oxidation worked as planned, but isolation of the acid chloride was
problematic as no acid chloride could be recovered. After purification, only the
carboxylic acid (188) was identified by 1H NMR. It was apparent that the acid chloride
was not stable and was readily converted back into the carboxylic acid with any source of
water, including moisture in the air.
94
O
HO
HO
OH
H
O
HO
152
Jones
O
O O
HO
187
O O
SOCl2
O
Cl
188
O
185
Scheme 54: Synthesis of acid chloride.50, 73, 89
Other ways ester 186 could be obtained could be through the use of coupling
reagents such as N,N-dicyclohexylcarbodiimide (DCC), 2,4,6-Tripropyl-1,3,5,2,4,6trioxatriphosphorinane-2,4,6-trioxide (T3P) or 1-[Bis(dimethylamino)methylene]-1H1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU). The esterification
of a carboxylic acid and an alcohol using DCC is known as a Steglich esterification.90 To
make ester 186 using DCC, we would need to use carboxylic acid 188 and couple it with
alcohol 184 (Scheme 55). The other reagents like T3P and HATU would work in the
same fashion.
O
OH
184
HO
O
188
DCC
DMAP
O
O
O O
O
186
Scheme 55: DCC coupling to synthesize ester 186.90
Another way to make ester 186 would be to perform a Mitsunobu reaction. A
Mitsunobu reaction couples an alcohol with a carboxylic acid using triphenylphosphine
and diethyl azodicarboxylate (DEAD). To make ester 186, we would need to use
95
carboxylic acid 188 and alcohol 184 and subject those to triphenylphosphine and DEAD
(Scheme 56).91
O
OH
184
HO
O
O
O
188
O O
Ph 3P
DEAD
O
186
Scheme 56: Ester 186 via a Mitsunobu reaction.91
If compound 186 were completed, two pathways could be envisioned to prepare
the next crucial intermediate. The product could either be brominated first, followed by
diazotization, or diazotization could be added prior to bromination. If we follow the
initial bromination pathway, compound 186 could be subjected to acid hydrolysis of the
ethylene ketal protecting group,92 then followed by bromination to provide the αbromomethyl ketone 189.78 Compound 189 could then be subjected to Davies
diazotization protocol, p-ABSA/base to introduce the diazo moiety alpha to the carbonyl,
forming bromo-diazo carbonyl 190.52 (Scheme 57)
O
O O
186
1. H
O
2. Br 2, MeOH
O
O
O
Br
p-ABSA, DBU
MeCN
189
Scheme 57: First attempt to make diazocarbonyl 190.52, 78, 92
O
O
190
N2
O
Br
96
Alternatively, introduction of the α-diazocarbonyl group prior to bromination
requires that compound 186 first be subjected to aqueous acid to deprotect the ethylene
ketal92 and then subjected to Davies protocol to provide the α-diazocarbonyl 191.52
Potassium bis(trimethylsilyl)amide could be used to make the enolate, which could be
trapped using TMSCl to provide the diazo enolether compound 192.86a Compound 192
could then be subjected to bromine to provide the bromo-diazo carbonyl 190.78 (Scheme
58)
O
O
O O
186
1. H
O
2. p-ABSA,
DBU
MeCN
O
O
N2
KHMDS
TBSCl, DCM
O
N2
Br 2, DCM
O
TBSO
O
191
O
192
O
O
N2
O
Br
190
Scheme 58: Second attempt to make diazocarbonyl 190.52, 78, 86a, 92
This product (190) could then be subjected to the cuprate addition enolether
product (177) used in an earlier sequence of 3,3-dimethylcyclohexan-1-one to give
compound 193.83 Once completed, this compound provides a scaffold that can further be
subjected to catalytic dirhodium catalysis. Initial ylide formation results from diazo
decomposition followed by intramolecular cycloaddition of the resulting ylide that would
result in formation of the pentacycle 194.37 Previous research in the McMills group has
shown that the oxygen bridge is vulnerable to samarium diiodide opening resulting in the
formation of the frondosin analog (195) (Scheme 59).37
97
OTBS
O
N2
177
O
O
Br
Rh(II) catalyst
O
O
N2
O
190
O
O
O
DCE
O
O
193
O
O
HO
O
SmI2
O
O
O
O
195
194
Scheme 59: Final steps towards the Frondosin B analog.37, 83
The actual synthesis started out fine with the indene (149) being converted into
the carboxylic acid (150) by the same pathway as in the previous synthesis and in good
yields.72 The reduction of the carboxylic acid to the alcohol (184) was problematic in that
good yields could not be obtained and only small amounts of the indene alcohol 184 were
obtained.77 Low yields could be due to the fact that the reagents were not dry enough to
have the reaction proceed to completion. Any water present in the reaction could quench,
or reduce the efficiency of LAH and the reduction cannot occur. At this point, other
pathways towards Frondosin B analogs were brought to the forefront and those syntheses
began in tandem while continuing this synthesis. Once the other syntheses showed more
promise, this synthesis was abandoned to focus on the other syntheses.
98
4.3: Benzofuran Synthesis towards Frondosin B
At this juncture, it was decided that a completely new synthetic strategy was
needed to synthesize these novel oxo- and carbocyclic compounds. It was decided to
work on a series of analogs that include the benzofuran found in Frondosin B. This
synthesis would proceed through the intermediacy of a brominated benzofuran ester and
an epoxy-alkene, which once put together could then undergo a cycloaddition reaction to
synthesize the Frondosin B analog.
O
O
O
CO2R
CO2R
O
201
O
200
199
Br
CO2R
O
196
N2
O
CO2R
N2
+
O
O
197
198
Scheme 60: Retrosynthesis towards a Frondosin B analog.
In Scheme 60, our retrosynthetic analysis shows that we can start from a
substituted benzofuran 196 followed by a lithium-halogen exchange to provide the
99
nucleophilic partner for the reactive epoxide (197). Once connected, the benzofuran
olefin (198), with our needed diazocarbonyl in place can react under dirhodium catalysis
to form an ylide (199), followed by intramolecular cycloaddition of the pendant olefin to
form the oxobridged compound 200. The bridging oxygen can then be cleaved to prepare
Frondosin B analog 201.37
The synthesis will be formed in several distinct sessions to provide all the
necessary reactants.
H
N
O
sulfur, heat
+
O
HCl
O
72%
O
N
O
S
203
202
Br
Acetic Acid
heat
O
204
OH
O
1. MeOH
H 2SO 4
2. H 2O
KOH
Ethyl Acetate
Br
N2
O
pABSA
O
O
O
NBS
O
O
O
Br 2
THF
206
O
HO
CO2R
N2
O
O
O
205
n-BuLi
oxidation
O
CO2R
N2
O
O
CO2R
O
Scheme 61: Synthesis of the benzofuran piece.78, 82, 93
O
CO2R
O
100
The synthesis begins with preparation of thioamide 203 from commercially
available acetylbenzofuran (202) and subjecting it to morpholine and sulfur (Scheme
61).93 This reaction proceeds through a Willgerodt-Kindler rearrangement (Scheme
62).94
O
O
enamine
O
N
O
N
N
formation
O
O
O
S
S
S 6
207
H
S S
6
SH
O
S
S6 SH
H
N
H H
N
O
O
H H
N
208
O
O
N
O
O
N
N
O
O
S6 S
HS
H
N
H
S
S6
O
SH
S
S6 SH
O
O
N
S
S
S5
SH
O
O
N
O
S
203
Scheme 62: Willgerodt-Kindler rearrangement mechanism to form thioamide 197.94
The Willgerodt-Kindler rearrangement mechanism begins with the formation of
the enamine 207. The enamine then attacks sulfur in the form of S8. The key step is the
formation of the three-membered nitrogen-containing ring in 208, where the morpholine
101
unit is rearranged. After the rearrangement of the morpholine, formation of the
thioamide 203 occurs (Scheme 62).94
Thioamide 203 was then converted to carboxylic acid 204 by dissolving it in
concentrated hydrochloric acid (HCl) and acetic acid, then heating the resulting
mixture.93 The resulting carboxylic acid 204 could never be purified, but the 1H NMR of
the crude reaction product showed conversion to the acid. The crude acid was carried
forward using a Fischer esterification to form the corresponding ester (205) in low but
manageable yields.93 Formation of the vinyl halide was attempted from the benzofuryl
ester with both NBS82 and elemental bromine78, providing no appreciable amount of the
vinyl bromide 206.
Our analysis of the results of these failed reactions are as follows. For the reaction
with elemental bromine, the first step of the desired mechanism is the push of electrons
from the oxygen of the benzofuran 205 through the alkene for attack of elemental
bromine to give structure 209. The bromide ion in solution then deprotonates at the
carbon with the bromine on it and reforms the double bond in 206. Crude 1H NMR shows
that this did not occur. Crude 1H NMR shows that only a small amount of starting
material remained, but a new peak arose at 4.85 ppm. This peak could be due to the
formation of an alkene outside of the benzofuran ring, next to the ester in 211. The
mechanism for this reaction would be deprotonation of the proton α to the ester (210)
(Scheme 63). Crude 1H NMR also shows the disappearance of the original methylene
unit.
102
Br Br
Br
Br
H
O
O
O
O
205
Br
O
O
O
O
O
206
209
Br
Br
Br
H
O
O
O
O
210
O
O
211
Scheme 63: Mechanism for bromination reaction.
As for the case with NBS as the brominating agent, our analysis of the 1H NMR
showed some disappearance of the methylene unit again with a peak showing an alkene
in that position as well. There was also an extra peak at 2.05 ppm, which could indicate
the presence of the succinimide unit on the molecule in the form of an amide 212
(Scheme 64) or as an enamine 213 (Scheme 65). We concluded with this data that there is
a mixture of the enamine as well as the amide as the resulting products.
103
O
O
N
N
Br
O
O
O
Br
H
O
O
O
O
O
N
Br
O
O
O
O
O
Br
Br
O
O
N
O
O
212
Scheme 64: Mechanism towards amide.
O
O
O
O
N
O
104
O
N
O
Br
Br
Br
O
O
O
O
N
O
O
H 2O
O
H
O
N
O
O
O
O
N
O
Br
O
O
O
N
O
213
Scheme 65: Mechanism towards enamine.
4.4: Salicylaldehyde approach towards the benzofuran ester
An alternate route was devised to assemble the benzofuryl moiety in Scheme 66.
This synthesis originated with salicylaldehyde (214) and reacted it with ethynyl
magnesium bromide, providing the propargyl aromatic 215 in low yield.95 After several
reactions, enough material had been collected to continue with the synthesis. Propargyl
arene 215 could be converted into the desired benzofuran ester 205 by using palladium
chemistry to form the benzofuryl moiety with PdI2, methanol and carbon monoxide under
pressure.96 This reaction was not attempted because of the use of high pressure carbon
monoxide and the small amount of starting materials we would be able to run in a single
105
reaction. Also, the esterification of carboxylic acid 204 from Scheme 61 worked well and
we could perform that reaction on a larger scale. Once the ester was in hand, the route is
the same, first brominating, then making the diazo using p-ABSA to give the desired
product.
O
OH
H
OH
214
O
BrMg
PdI 2
20%
MeOH
CO
OH
215
O
Br 2
Br O
O
or NBS
O
p-ABSA
DBU
O
Br O
O
O
N2
205
Scheme 66: Salicylaldehyde approach to the benzofuran ester.95-96
4.5: Epoxyolefin synthesis
Our analysis of the coupling partner provided a possible synthesis of an epoxide
to couple, providing the ylide cyclization precursor.
106
TBSCl
Br
OH
Hunig's Base
216
O
Mg
Br
OTBS
217
Me 2TiCl2
acid
OTBS
219
OH
BrMg
or
Me 2Zn
OTBS
O
+
OH
NCS
OTBS
H
OTBS
218
PCC
Corey-
O
Chaykovsky
Epoxidation O
197
Scheme 67: Synthesis of epoxyolefin.29b, 67-68, 84, 97
To prepare epoxyolefin 197, bromoalcohol 216 was protected as its TBS ether
(217)84, followed by Grignard formation and addition to acrolein.97a Unfortunately,
acrolein has become an unavailable item of commerce. Our synthetic scheme is shown in
66. Grignard formation followed by 1,2-addition to the aldehyde of acrolein, would
provide the heptenyl diol and protection of the primary alcohol would provide 218.97a
Oxidation with NCS67, gem-dimethylation with titanium or zinc reagents would form the
dimethyl heptenyl alcohol 219.29b Deprotection with mineral acid or fluoride (F-)
followed by oxidation to the aldehyde using PCC68 and finally Corey-Chaykovsky
epoxidation97b would likely have generated the coupling epoxide (197) needed.
107
O
HCl
O
OH
BrMg
69%
87%
220
OH
HO
222
221
TBSCl
OH
imidazole
DMF
RO
223
MnO 2
1. deprotection
2. oxidation
DMP
RO
225
226
Jones
O
Me 2TiCl2
RO
O
PCC
224
Corey-Chaykovsky Epoxidation
O
197
Scheme 68: New route to the epoxyolefin.68, 84, 89, 97a, 98
An alternate route was devised to make the epoxyolefin 197 compound (Scheme
68). Commercially available 3,4-dihydro-2H-pyran (220) was subjected to HCl to
provide lactol 221 in good yields.98a Crude 1H NMR also shows the aldehyde peak for the
open chain form of this structure. Vinylmagnesium bromide was added to the lactol to
generate heptenyl diol 222.97a The allylic alcohol could be oxidized using manganese
dioxide, since this reagent specializes in oxidizing allylic alcohols.98b The crude 1H NMR
of the reaction mixture only showed the starting material and no oxidized product. Due
to this fact, the primary alcohol of the diol was protected using TBSCl to provide the
mono-protected allylic alcohol 224.84 The oxidation of the alcohol was troublesome.
Manganese dioxide,97a PCC,68 Dess-Martin Periodinane (DMP),98c and Jones reagent89
were ineffective in oxidizing the allylic alcohol to the enone. In the case of the TMS- or
TBS-protected primary alcohol, it was determined that bis protection or a gross mixture
108
of products resulted, meaning oxidation could not occur on the protected allylic alcohol.
1
H NMR still only showed unoxidized starting material. The protection step was then
attempted with the more bulky protecting reagent tert-butyldiphenylsilyl chloride
(TBDPSCl) rather than TBSCl with the assumption that the more bulky group would
selectively protect the primary alcohol over the secondary allylic alcohol.84 This proved
not to be the case as a gross mixture of protected products again were found by 1H NMR.
The oxidations were attempted again, but none of the oxidants provided the enone due to
protection of the allylic alcohol. 1H NMR still showed the unoxidized starting material.
Looking back on this synthesis of the epoxyolefin, the troublesome step was the selective
protection of the primary alcohol over the secondary alcohol. Since we used TBDPSCl as
a group to selectively protect the primary alcohol versus the secondary allylic alcohol,
this synthesis ran into problems because of two unprotected alcohols that could not
selectively be protected. The rest of the synthesis would follow in a similar path as those
previously delineated. Since this synthesis was troublesome, a new route was devised to
overcome the selective protection problem.
109
OMe
HN
.HCl
Me
O
O
HO
AlMe3
10%
225
O
O
N
OMe
TBSCl
RO
N
OMe
226
BrMg
1. deprotection
2. oxidation
RO
RO
O
O
Me 2TiCl2
227
228
224
Corey-Chaykovsky Epoxidation
O
197
Scheme 69: Weinreb amide approach to epoxyolefin.29b, 68, 84, 97, 99
An additional procedure (Scheme 69) was envisaged for the formation of the
epoxyolefin 197 using a Weinreb amide as the electrophilic intermediate. This synthesis
begins with commercially available δ-valerolactone (225) followed by opening the ester
with the help of a Lewis acid, trimethylaluminum, and methoxymethylamine
hydrochloride to form the Weinreb amide 226.99 This reaction proceeded, but with rather
poor overall yield. The use of trimethylaluminum is precluded due to cost (3 equivalents
required) and difficulty in large-scale reaction work-up. If the Weinreb amide 226 were
available, the alcohol would be protected84 and then the protected Weinreb amide
subjected to methylmagnesium bromide to form the α-β unsaturated ketone 224.97a
Dimethyl titanium dichloride would be used to gem-dimethylate the ketone to give alkene
227.29b The alcohol would be deprotected using HCl and oxidized using PCC68 to provide
110
aldehyde 228. A Corey-Chaykovsky epoxidation would then be utilized to transform the
aldehyde into the final epoxide intermediate (197).97b
4.6: Faveline analog synthesis
At this point, a route was devised to synthesize a truncated Faveline structure.
This was due to the simplistic look and elimination of the furan ring from the Frondosin
B analogs. This synthesis was performed in parallel with the other Frondosin B
syntheses. Faveline and its methyl ether are isolated from the bark of the Brazilian plant
Cnidoscolus Phyllacanthus. Faveline has shown activity against P-388 murine leukemia
cells.100
The synthesis of the truncated frondosin analog faveline is provided through
commercially available methyl 2-(2-bromophenyl)acetate (229). Reduction of the ester
with lithium aluminum hydride was achieved to generate the primary alcohol 230.77 The
primary alcohol was protected using TBSCl/imidazole to give the TBS protected alcohol
231 in good yields (Scheme 70).84
Br
LAH
O
O
229
Br
THF, 30%
TBSCl
OH
Br
imidazole, 75%
230
231
OTBS
Scheme 70: Synthesis of TBS-protected alcohol 231.77, 84
Our simple coupling partner derived from 2-(hex-5-en-1-yl)oxirane (232) was
subjected to dibromoborane dimethylsulfide to open the epoxide ring and to brominate
alpha to the resulting alcohol, to give the bromohydrin 233 and its regioisomer 234 in
111
good yields with an 85:15 ratio for the desired product 233.101 The alcohol of the
bromohydrin was then protected with MOMCl to give the protected bromohydrin 222 in
excellent yields (Scheme 71).102 The two regioisomers could not be separated and were
both carried forward into the next reaction.
1. BHBr 2-SMe2
79%
2. MOMCl
81%
OMOM
+
Br
O
232
233
Br
MOMO
234
Scheme 71: Ring opening of epoxide to provide bromohydrin 233.101-102
A bromo-lithium exchange was then attempted using n-BuLi, but with no
apparent product. The lithium base was replaced with t-BuLi, but again, the exchange
was not observed (Scheme 73).103 Crude 1H NMR showed the proteo product meaning a
small amount of the lithium exchange did occur, but was being quenched with a proton
source before it could attack the electrophilic epoxide. It could also be that the epoxide
232 was not electrophilic enough for the lithium species to attack. Another option would
be to use the aldehyde rather than the epoxide, to make the carbon more electrophilic.
Another problem that could have occurred was an elimination reaction through an E1cB
mechanism. Once the bromo-lithium exchange happened to give the resulting carbanion
235, elimination could occur through the E1cB mechanism giving the diene product 236
(Scheme 72).
112
n-BuLi
OMOM
OMOM
Br
236
235
Scheme 72: Possible E1cB elimination mechanism.
The protected bromohydrin 233 was then coupled to the aryl bromide using
tetrakistriphenylphosphine palladium, albeit in poor yields (Scheme 73).104 The poor
yields of this coupling reaction could be due to the fact that both regioisomers of the
bromohydrin were present in the reaction. This could reduce the efficiency of the
palladium for catalyzing the reaction. This synthesis was abandoned due to the poor
yields in the palladium coupling reaction. Starting material costs and availability,
especially the oxirane, as well as the number of steps needed to get to the coupling step
all played in a role in the decision to abandon this synthesis.
RO
Pd(PPh 3)4
27%
OTBS
R= H, MOM
231
233
1. t-BuLi
OTBS
OMOM
Br
RO
Br
2.
O
OTBS
232
R= H, MOM
Scheme 73: Attempts to couple bromohydrin 232 and aryl bromide 231.103-104
To continue the synthesis, deprotection of the silyl protecting group using TBAF
would provide the alcohol.59 Oxidation of the resulting primary alcohol to the carboxylic
acid using Jones reagent,89 followed by Fischer esterification procedure,74 would result in
the formation of ester 237. The diazo moiety would be introduced alpha to the carbonyl
113
of the ester using Davies conditions with p-ABSA and DBU.52 Deprotection of the MOM
group would reveal an alcohol that could be oxidized to the necessary ketone in 238. At
this point, we would have the required precursor needed to proceed with the ylide
formation/cycloaddition reaction to give the final desired product. (Scheme 74)
RO
1.MOMCl
O
MOMO
1. pABSA
OTBS
R= H, MOM
TEA
2. Deprotection
3. [O]
4. MeOH, H +
O
DBU
2. TFA
3. [O]
O
237
O
O
N2
238
Rh 2L 4
O
CO2R
O
CO2R
Scheme 74: Final steps towards the Faveline analog.52, 59, 74, 89
4.7: Stetter reaction approach towards Frondosin B analog
Since the previous routes to the desired Frondosin products did not work. A new
synthesis was devised to run parallel to the Faveline synthesis to the core structure of
Frondosin B. This route uses a Stetter reaction to form the 5-membered oxygencontaining ring of the benzofuran.
In a final approach to Frondosin B and its analogs, commercially available methyl
propiolate (239) was subjected to salicylaldehyde (214) in the presence of N-methyl
morpholine to provide the ester (240) in very good yields.105 The five-membered ring was
114
then cyclized using an intramolecular Stetter reaction with thiazolium chloride (241) used
as a catalyst.106 This reaction proceeded to give the benzofuran intermediate 242.
(Scheme 75)
HO
O
H
OH
214
CO2Me
239
96%
S
O
H
241
O
O
240
O
Cl-
N
Bn
O
O
O
42%
O
242
Scheme 75: Formation of the benzofuran via a Stetter reaction.105-106
With the benzofuran intermediate (242) obtained, it was subjected to a Grignard
reagent 243 made from the epoxide attempted in an earlier sequence.97a The epoxide
would be opened using the same procedure as the previous synthesis by using
dibromoborane dimethyl sulfide to provide the resulting bromohydrin (Scheme 71).102
The alcohol of the bromohydrin could be protected using TBSCl and the Grignard
reagent 243 could be made from the resulting protected bromohydrin. The reaction of the
Grignard reagent 243 and the benzofuran compound 242 did not go smoothly as no
product could be obtained. It was determined that reaction of benzofuran 242 and
Grignard 243 resulted in a gross mixture of products (Scheme 76). It is also possible that
an E1cB elimination occurred on this substrate as well once the Grignard was made. This
is very similar to the elimination in Scheme 72.
115
TBSO
HO
BrMg
O
O
O
TBSO
HO
OTBS
243
O
242
OH
+
O
O
TBSO
O
TBSO
O
O
OH
O
TBSO
TBSO
Scheme 76: Grignard addition to 242.
A model reaction was attempted using 242 and ethynyl magnesium bromide with
the hopes that it would attack the ketone on the five-membered ring selectively over the
ester functionality. 1H NMR of this model reaction showed that attack occurred not only
at the ketone of the five-membered ring, but also at the ester as well, giving a gross
mixture of products (Scheme 77).
O
O
O
O
MgBr
+
+
O
242
O
O
O HO
OH
OH
O
HO
O
Scheme 77: Model reaction of ethynylmagnesium bromide and 242.
The rest of the synthesis included elimination to form the olefin, which will
greatly enhance the stability of the diazo,107 introduction of the diazo next to the carbonyl
of the ester using Davies conditions, p-ABSA and DBU,52 followed by deprotection and
116
oxidation of the resulting alcohol to give 244. At this point, the required precursor for the
rhodium-catalyzed reaction would be obtained. A rhodium catalyst could then be used to
give the final desired product. (Scheme 78)
1.POCl 3
pyr
2. pABSA
DBU
TBSO
HO
O
O
O
3. TBAF
4.[O]
O
Rh 2L 4
N2
O
O
O
CO2R
O
O
CO2R
O
O
244
Scheme 78: Grignard attack, elimination, diazotization and cycloaddition.52, 97a, 107
While both intermolecular and intramolecular approaches have been attempted,
the advanced intermediates needed for the synthesis of truncated Frondosin B analogs
have not been obtained in appreciative yields. In the case of the desoxy-Frondosin B
analog, we ran into issues with formation of the silyl enolether. We could only obtain
very small amounts of the enolether by 1H NMR and could not isolate it (Schemes 42, 46,
& 50). We also had issues with cuprate formation and attack of 3-methylcyclohex-2-en1-one (Scheme 51). It was determined that the cuprate did not form in situ and rather, the
Grignard reagent attacked in a 1,2 fashion rather than the 1,4-addition that was desired.
Issues were also apparent in the formation of ester 186 through the use of an acid
chloride. The required acid chloride could not be obtained, but if time had allowed, other
attempts could have been made including using coupling reagents such as DCC (Scheme
55), T3P or HATU, as well as a Mitsunobu reaction (Scheme 56) to form ester 186.
117
In our attempts to make the benzofuran derivative, the reaction sequence began
with a flourish as the thioamide 203 was obtained in good yields. This reaction proceeded
through a Willgerodt-Kindler rearrangement to give the thioamide (Scheme 62). We had
issues brominating the 5-membered ring later in the reaction sequence. It was determined
that by using elemental bromine as a bromination agent, we ended up with the wrong
elimination product. Rather than eliminating to form the vinyl bromide, it eliminated to
give the α,β-unsaturated ketone (Scheme 63). With the use of NBS as the brominating
agent, it was determined that with ended up with a mixture of amide formation (Scheme
64) as well as enamine formation (Scheme 56), but not giving the desired product
(Scheme 65). There was also the issue of the attempts at oxidation of the allylic alcohol.
It was determined that there was a gross mixture of mono- and bis-protected alcohols as
well as completely unoxidized starting material. The fact that two alcohols were present
and selectivity of the primary over the secondary alcohol could not be obtained (Scheme
68). The last setback encountered was with the bromo/lithium exchange of the Faveline
intermediate (Scheme 71). It was determined by 1H NMR that a small amount of the
proteo compound was obtained, meaning that some bromo/lithium exchange did occur,
but was immediately quenched by a proton source. It was also concluded that the epoxide
may not have been electrophilic enough for the lithium species to attack and the aldehyde
equivalent of the epoxyolefin should be attempted next. Another possibility is an
elimination reaction that proceeds through an E1cB mechanism to give the dialkene
product (Scheme 72).
118
Finally, in the Stetter reaction pathway, it was concluded that Grignard attack of
the ketone on the five-membered ring did not solely occur. A model reaction attempted
with ethynyl magnesium bromide showed a mixture of reaction products with attack of
the Grignard reagent at the ketone of the 5-membered ring as well as the ester on the
chain (Schemes 76 & 77). This resulted in a gross mixture of products that was not
isolable.
119
CHAPTER 5: OTHER PROJECTS
5.1: Albomycin: Synthesis of a C7N amino acid subunit
OH OH
CO2H
HO
OH OH
NH 2
245
Figure 23: Structure of the C7N Unit of Albomycin.108
Albomycin is an antibiotic that belongs to the class of sideromycins.
Sideromycins are compounds that have iron carriers that are attached to antibiotic
moieties. Albomycin has been shown to be active against bacteria that have a transport
system that consists of ferric hydroxamate. Since albomycin is an iron carrier, bacteria
with ferric hydroxamate will transport the antibiotic albomycin, until they die.
Albomycin has been effective in clearing both Gram-positive and Gram-negative
bacterial infections, which allows the immune system to remove any bacteria that is
resistant to albomycin.109
Amino penta-ol 245 (Figure 23) is one subunit of Albomycin 7, prepared
biogenetically through the enzyme-catalyzed reaction between either serine and threose
or xylose and glycine (Scheme 79).108
120
HO
H 2N
CO2H
OH
HO
Serine
Alb7
+
H 2N
OH
CH2OH
OHC
HO
H 2N
Glycine
CH2OH
OH
Alb7
+
CO2H
OH
245
OH
OHC
CH2OH
OH OH
Xylose
C7N amino acid
Threose
CO2H
Scheme 79: Proposed albomycin biosynthetic pathway and functions of alb 7
enzyme.108
The synthesis of the C7N amino acid subunit is important for a determination of
the enzymatic products of this antibiotic compound. Currently, a standard is needed to
develop an assay regarding the production of the C7N amino acid and whether it is one of
the products of the enzymatic reaction. The synthesis of this C7N amino acid is shown in
Scheme 80.
O
H
O
O
O
+
Boc
N
OTBS
1. SnCl 4, Et 2O
2. TBS-Cl, imidazole
TBSO
O
N
Boc
O
O
O
O
O
247
248
246
1. KMnO 4, 18-crown-6
2. LiOH, THF
3. NaIO 4, SiO2, DCM
OH OH
CO2H
HO
OH OH
245
Scheme 80: Proposed synthesis of the C7N Unit.108
NH 2
121
Our proposed synthesis of the penta-ol subunit begins with aldehyde (246) and
protected lactam (247); combined in a tin-catalyzed Aldol reaction, followed by
protection of the pendant alcohol formed with tert-butyldimethylsilyl chloride to provide
product (248). Oxidation of the lactam unit with potassium permanganate, utilizing
cation sequestration with 18-crown-6, followed by global deprotection of the acetonide
groups with lithium hydroxide and finally sodium periodate was used as a last oxidant to
give the desired C7N final product (245). The syntheses of aldehyde 246 and lactam 247
will be described in distinct sections. The aldehyde synthesis is shown in Scheme 81.
O
HO
OH
OH
OH
O
1) HCl
2) propane 1,3-dithiol
r.t, 24h, 60%
3) 2,2 DMP
S
S
MeI, CaCO 3
O
O
O
249
250
O
H
O
O
O
CuCl2
CuO
O
NCS
AgNO3
246
Scheme 81: Aldehyde Synthesis from L-arabinose.110
Preparation of the aldehydic coupling partner began with L-arabinose (249). Larabinose 249 was treated with hydrochloric acid while in the presence of propane-1,3dithiol to provide dithiane (250)110 in decent yields. Three separate deprotection methods
were attempted to provide the aldehyde necessary for further reaction. None of the
methods provided any of the desired aldehyde (246). Our first generation was initiated
through the alkylation of the dithiane moiety via the addition of iodomethane in
acetonitrile in the presence of calcium carbonate.110 After several attempts, the reaction
122
showed no sign of aldehyde presence by 1H NMR spectroscopy, the crude reaction
mixture did not show any aldehyde proton in the range of 9-11 ppm. The second
cleavage method attempted was the addition of N-chlorosuccinimide (NCS) and silver
nitrate in acetonitrile to provide the desired aldehyde (246).111 Again, 1H NMR did not
show any signature aldehyde peak. Our third attempt to make the aldehyde was through
the addition of copper(II) chloride and copper oxide in acetone to the dithiane (250).112
1
H NMR did not show the formation of any apparent aldehyde peak. Finally, the
deprotection was attempted using acyl chloride, and sodium nitrite to give the desired
product.113 Unfortunately, this method did not work as well. After some literature
searching, it was found that dithioketals are notoriously difficult to deprotect and
sometimes required very specific conditions that can change depending on the
substrate.114 A better approach to this problem would have been to protect the aldehyde
using ethylene glycol to give the resulting dioxolane, which can readily be removed with
acid.
After four unsuccessful attempts to reveal the aldehyde through deprotection of
the dithiane, another synthetic pathway was sought. The second generation began with a
new carbohydrate, gluconolactone (Scheme 82).
123
O
HO
O
HO
O
OH
2,2-DMP
p-TSA, acetone
MeOH
HO
O
OCH3
O
LAH
THF
HO
O
O
OH
251
OH
O
O
O
O
252
253
NaIO 4
O
H
O
O
DCM
NaHCO 3
O
O
246
Scheme 82: Aldehyde synthesis from gluconolactone.115
Commercially available D-(+)-glucono-1,5-lactone (251) was reacted with 2,2dimethoxypropane (2,2-DMP) in the presence of a catalytic amount of p-toluenesulfonic
acid (p-TSA) in acetone/methanol to generate bis-acetonide hydroxyester 252 in good
yields.115a Bis-acetonide hydroxyester 252 was reduced with lithium aluminum hydride
(LAH) to provide diol 253.115a Sodium periodate (in DCM), in the presence of sodium
bicarbonate cleaved the diol formed in the prior reduction to generate aldehyde (246)
albeit in relatively low overall yield.115b The synthesis of the protected lactam is shown in
Scheme 83.
124
H
N
H 2O2, H 2O
O
H
N
Boc 2O
O
Boc
N
MeCN, DMAP
254
256
255
NaH
THF
Boc 2O
O
Boc
N
TBSOTf
256
lutidine
TBSO
Boc
N
247
Scheme 83: Protected lactam formation.
116
To synthesize the pyrrole based silyl enolether, pyrrole (254) was oxidized with
hydrogen peroxide in water to give lactam 255 in satisfactory chemical yield.116a The
resulting lactam was treated with di-tert-butyl dicarbonate (Boc2O) and catalytic
dimethylaminopyridine (DMAP) in acetonitrile to give the Boc-protected lactam 256.116a
Unfortunately, this protection procedure provided none of the Boc-protected lactam
needed. Since the t-butyl resonance of the protecting group did not appear in the 1H NMR
spectrum, it was surmised that initial reaction conditions were not basic enough to
deprotonate the nitrogen of the lactam and allow for formation of the Boc-protecting
group. As a result, sodium hydride, a stronger base, was used to deprotonate the N-H of
the lactam, providing the nucleophile needed to react with the Boc2O and allow formation
of the protected lactam.116b This reaction worked to provide a small amount of material
that was combined over several runs to provide material for the subsequent step. The
final step involved a base initiated deprotonation and subsequent trapping of the resulting
125
enolate with TBSCl. This reaction was performed with 2,6-lutidine and tertbutyldimethylsilyl trifluoromethane (TBSOTf).116a The reaction proceeded to give trace
amounts of the desired product. The lack of significant amount of product was concluded
to be due to the basicity of the conditions again. 2,6-lutidine was not basic enough to
deprotonate and therefore could not form the enolate that needed to be trapped. If time
had allowed, a stronger base would have been attempted to form the enolate, followed by
trapping with TBSCl. Since appreciable amounts of material for the requisite aldehyde
and protected lactam could not be obtained, the project was postponed, while a new
project was started.
5.2: Synthesis of 1-(azetidin-1-yl)-2-diazoethan-1-one
O
N
H
N2
257
Figure 24: 1-(azetidin-1-yl)-2-diazoethan-1-one.117
Diazoacetamides, like 1-(azetidin-1-yl)-2-diazoethan-1-one (257) (Figure 24),
have been expected to undergo photochemical or thermal Wolff rearrangements or C-H
insertions.117 It was discovered that non-cyclic N,N-dialkyl containing diazoacetamides
undergo the C-H insertion reaction, whereas cyclic amides suppress the insertion
reactions and favor the Wolff rearrangements to ketenes.117
1-(azetidin-1-yl)-2-diazoethan-1-one needed to be synthesized as a standard for
spectroscopic identification of starting material prior to light induced carbene
126
formation.117 Despite the small nature of the molecule, it is a relatively difficult synthesis
for several reasons, including the availability of azetidine. The sequence (Scheme 84)
began with preparation of the precursor to succinimidyl diazoacetate from commercially
available starting materials methylbenzenesulfonylhydrazide (258) and glyoxylic acid
(259) being heated together with acid to generate the sulfonylhydrazono acid 260118,
followed by acid chloride formation with thionyl chloride to prepare glyoxylic acid
chloride (p-toluenesulfonyl)hydrozone 261.118 The acid chloride provides the
electrophilic center to add the hydroxysuccinimide moiety, providing the diazoacetate
reagent needed to generate the azetidine diazomide.
O O
S
NH 2
N
H
O
+
HCl
OH
H
O O
S
N
N
H
O
SOCl2
OH
O O
S
N
N
H
O
258
259
O
Cl
261
260
O
N OH
O
262
O
HN
O
H
N O
N
N2
257
Et 3N
O
O
263
N2
H
Scheme 84: Original synthesis of 1-(azetidin-1-yl)-2-diazoethan-1-one.118
There were a number of difficulties found with this synthesis. Initial isolation of
the acid chloride was especially difficult as only the carboxylic acid could be isolated.
This could be due to the fact that water in solution of in the air came into contact with the
acid chloride, therefore converting it back to the carboxylic acid. To remedy this
127
situation, the acid chloride was generated in situ, immediately reacted with Nhydroxysuccimide (262) followed by work-up to attempt to isolate the diazoacetate in a
one-step procedure.119 It appears that this provided a small amount of the diazoacetate
263. Crude 1H NMR shows a broad peak at 5.13 ppm, which is the normal position for a
proton directly bound to a diazocarbonyl group. The 1H NMR spectrum also shows peaks
consistent with those of a tosyl group. The reaction yield was limited and purification of
the diazoacetate difficult. It was surmised that the acid chloride was not being generated
in situ due to wet solvent conditions.
We then attempted to couple the tosylhydrazono acetic acid (260) directly with Nhydroxysuccinimide (262) (Scheme 84). The tosylhydrazono acetic acid (260) was
directly subjected to N-hydroxysuccinimide (262), using coupling reagent N,N'Dicyclohexylcarbodiimide (DCC) to provide the diazoacetate 263.120 Again, this reaction
failed to give the desired product. DCC coupling typically couples carboxylic acids and
alcohols or amide to provide the corresponding ester or amide. Since the electronics of
the N-hydroxysuccinimide are different than either an alcohol or an amide, the coupling
reaction did not proceed. We chose instead to make the final product in a more direct
fashion, subjecting the tosylhydrazono acetic acid (260) to azetidine (via the HCl salt)
and DCC to give N'-(2-(azetidin-1-yl)-2-oxoethylidene)-4methylbenzenesulfonohydrazide (264).120 This reaction produced a low yield product, so
we sought to find an additional pathway to the diazotized azetidine. DCC coupling gave a
12% yield showing the reaction did work, but that a better coupling reagent was needed.
128
If time had allowed, T3P or HATU would have been attempted to see if those coupling
reagents would have given a better yield of the desired product.
O
O
N OH
N O
O
O
263
N2
O
262
H
DCC
O O
S
N
N
H
HN
O
OH
DCC
12%
260
O O
S
N
N
H
O
N
264
Scheme 85: Coupling reactions.120
Since none of these reactions provided a reasonable path to the diazoamide, a new
synthesis was devised (Scheme 86). Beginning with commercially available methyl 3chloro-3-oxopropanoate (265) and subjecting it to azetidine, the two partners were
coupled to form the amide 266 in excellent chemical yields.121 Amide 266 was subjected
to Davies conditions to prepare diazotized compounds by treatment with p-ABSA and
triethylamine to give the diazo 267.52 Lithium or sodium hydroxide can be used to form
the decarboxylated diazoamide (257) from the amidoester starting material.122 This
reaction appears to be more promising for brevity and overall yield and is still under
investigation.
129
HN
O
O
N
Cl
266
O
p-ABSA
O
O
265
O
O
TEA
N
O
O
LiOH
O
N2
267
Scheme 86: New route to 1-(azetidin-1-yl)-2-diazoethan-1-one.52, 121-122
H
N
N2
257
130
EXPERIMENTAL
General materials and methods:
All reactions were carried out under a nitrogen atmosphere and anhydrous conditions
unless otherwise noted. Acetonitrile (MeCN) was dried over calcium hydride and then
distilled. Dichloromethane (DCM) and tetrahydrofuran (THF) were dried using Solv-Tek,
Inc. column purification/drying system, which uses low-pressure nitrogen or argon gas to
force solvents through various filter materials that remove moisture and impurities.
Reagents purchased from commercial sources were used without further purification
unless otherwise noted. Analytical TLC was performed on 0.25 mm silica gel (60 F254)
plates purchased from EMD Chemicals, Inc. UV light and potassium permanganate
solution (1.5 g KMnO4, 10 g K2CO3, 1.25 mL 10% NaOH in 200 mL H2O) as visualizing
agents. Flash chromatography was carried out using Merck silica 60 (230-400 mesh). 1H
NMR spectra were recorded at 300 MHz on a Bruker AVANCE-300 spectrometer. 13C
NMR spectra were recorded at 75 MHz. Chemical shifts (δ) are quoted in parts per
million (ppm) downfield from tetramethylsilane (TMS). Multiplicities are abbreviated as
follows: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet or overlap of nonequivalent resonances; br, broad. Infrared spectra were obtained on a Shimadzu FTIR8400 spectrometer as neat oils.
131
O
O
3-(pent-4-en-1-yl)pentane-2,4-dione (110)54
2,4-pentanedione (1 g, 10 mmol) in 20 mL ethanol was cooled to 0°C and 5bromopentene (1.49 g, 10 mmol) was added along with sodium ethoxide (680 mg, 10
mmol). The reaction was allowed to stir at 0°C for 2 hours, and then let warm to room
temperature and let stir overnight. Dichloromethane was added and the mixture was
washed with water, sodium bicarbonate and brine and the combined organic layers were
dried over sodium sulfate, filtered and concentrated. The residue was purified by silica
gel chromatography eluting with 10% ethyl acetate in hexanes to give 3-(pent-4-en-1yl)pentane-2,4-dione (574 mg, 34%). 1H NMR (300 MHz, CHLOROFORM-d) δ ppm
1.25 - 1.40 (m, 2 H) 1.42 - 1.54 (m, 2 H) 1.80 - 1.92 (m, 2 H) 2.19 (s, 6 H) 3.58 - 3.67 (m,
1 H) 4.95 - 5.13 (m, 2 H) 5.67 - 5.89 (m, 1 H).
O
O
HO
3-(5-hydroxypentyl)pentane-2,4-dione (111)47
132
A round-bottomed flask was charged with 5 mL THF and flushed with nitrogen. Borane
(1 M in THF) (11.50 mg, 0.832 mmol) was added along with 3-(pent-4-en-1-yl)pentane2,4-dione (140 mg, 0.832 mmol). Hydrogen peroxide (28.29 mg, 0.832 mmol) was then
added and the reaction mixture was allowed to stir for one hour. Afterwards, sodium
hydroxide was added to the mixture to destroy acidic materials. The mixture was washed
with water, sodium bicarbonate and brine and the combined organic extracts were dried
over sodium sulfate, filtered and concentrated. The residue was purified by silica gel
chromatography eluting with 50% ethyl acetate in hexanes to give 3-(5hydroxypentyl)pentane-2,4-dione (105 mg, 68%). 1H NMR (300 MHz, CHLOROFORMd) δ ppm 1.26 - 1.32 (m, 2 H) 1.35 (br. s., 2 H) 2.10 (s, 6 H) 3.57 - 3.68 (m, 1 H) 4.65 5.11 (m, 1 H) with some buried protons.
O
O
N
OMe
(E)-6-acetyl-7-oxooctanal O-methyl oxime (119)53
6-acetyl-7-oxooctanal (50 mg, 0.27 mmol) was placed in a round-bottomed flask with
ethanol (1 mL) and methoxyamine hydrochloride (38 mg, 0.459 mmol) and heated to
55°C. A pre-made solution of sodium carbonate (20 mg) in 0.5 mL water was added via a
dropping funnel over a period of 10 minutes. The mixture was stirred for 2.5 hours at
60°C, then filtered through a frit, washed with ethanol and evaporated. Water (1 mL) was
133
added and the mixture was stirred at 70°C for 1 hour, then let cool to room temperature.
(E)-6-acetyl-7-oxooctanal O-methyl oxime (2 mg, 2%) was isolated by filtration and air
dried. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.25 (s, 2 H) 2.46 (s, 6 H) 3.79 3.84 (m, 3 H) 6.88 (s, 1 H) with some buried protons.
O
O
O
O
3-(4-(1,3-dioxolan-2-yl)butyl)pentane-2,4-dione (120)50
In a round-bottomed flask, 6-acetyl-7-oxooctanal (2 g, 10.86 mmol), ethylene glycol (674
mg, 10.86 mmol), 5 mL benzene and para-toluenesulfonic acid (1 mg, 0.005 mmol) were
placed. The flask was attached to a Dean-Stark trap under a condenser. The reaction
mixture was refluxed until close to the theoretical amount of water (0.2 mL) was
collected. The mixture was cooled to room temperature, washed with 15% sodium
hydroxide and water. The combined organic layers were dried over magnesium sulfate,
filtered and concentrated. The residue was purified by silica gel chromatography eluting
with 10% ethyl acetate in hexanes to give 3-(4-(1,3-dioxolan-2-yl)butyl)pentane-2,4dione (879 mg, 35%). 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.10 (s, 6 H) 3.80
- 4.05 (m, 4 H) 5.01 - 5.11 (m, 1 H) with some buried protons.
Br
OTBS
134
((5-bromopentyl)oxy)(tert-butyl)dimethylsilane (130)60
To a stirred solution of 5-bromopentanol (100 mg, 0.598 mmol) and iodine (25 mg, 0.2
mmol) in dichloromethane (2 mL) was added tert-butyldimethylsilyl chloride (72 mg,
0.478 mmol) in dichloromethane (2 mL) dropwise over 5 minutes. After 1 hour, finely
powdered sodium thiosulfate (180 mg, 1.138 mmol) was added and the mixture stirred
for an additional 30 minutes. The mixture was filtered through a plug of silica and the
filter cake was washed with dichloromethane (5-10 mL). The solvent was evaporated
under reduced pressure. The residue was purified by silica gel chromatography eluting
with 10% ethyl acetate in hexanes to give ((5-bromopentyl)oxy)(tert-butyl)dimethylsilane
(111 mg, 66%). 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.04 - 0.07 (m, 6 H)
0.86 - 0.88 (m, 9 H) 1.36 - 1.63 (m, 4 H) 1.73 - 1.93 (m, 2 H) 3.37 (td, J=6.47, 4.06 Hz, 2
H) 3.51 - 3.68 (m, 2 H)
Br
OTs
5-bromopentyl 4-methylbenzenesulfonate (130a)123
A round-bottomed flask equipped with a rubber septum and a stir bar was charged with
5-bromopentanol (500 mg, 2.995 mmol) and dichloromethane (5 mL). The solution was
cooled in an ice bath to 0°C while dimethylaminopyridine (18 mg, 0.14 mmol) and tosyl
chloride (570 mg, 2.99 mmol) were added. Triethylamine (3.63 g, 35.85 mmol) in
dichloromethane (5 mL) was added dropwise to the mixture at 0°C. The mixture was
stirred for 2 hours and poured into a mixture of ice (5 mL), water (5mL) and 2M
hydrochloric acid (2.5 mL). The aqueous layer was extracted with dichloromethane (5
135
mL) and the combined organic layers were washed with brine (2 x 5 mL), dried over
magnesium sulfate and concentrated. The residue was purified by silica gel
chromatography eluting with 20% ethyl acetate in hexanes to give 5-bromopentyl 4methylbenzenesulfonate (721 mg, 75%). 1H NMR (300 MHz, CHLOROFORM-d) δ ppm
1.34 - 1.46 (m, 2 H) 1.55 - 1.67 (m, 2 H) 1.68 - 1.80 (m, 2 H) 2.38 (s, 3 H) 3.20 - 3.34 (m,
2 H) 3.97 (t, J=6.33 Hz, 2 H) 7.22 - 7.33 (m, 2 H) 7.72 (d, J=8.12 Hz, 2 H).
O
N
O
1-(benzo[d][1,3]dioxol-5-yl)-N-cyclohexylmethanimine (134)64
Piperonal (1 g, 6.66 mmol) and cyclohexylamine (790 mg, 7.99 mmol) were placed in a
round-bottomed flask. The solution was distilled azeotropically by the literature
procedure124 and water was removed. The crude 1-(benzo[d][1,3]dioxol-5-yl)-Ncyclohexylmethanimine (1.37 g, 89%) was used in further syntheses. 1H NMR (300
MHz, CHLOROFORM-d) δ ppm 1.09 - 1.37 (m, 3 H) 1.40 - 1.53 (m, 2 H) 1.56 - 1.69
(m, 3 H) 1.70 - 1.82 (m, 2 H) 2.99 - 3.15 (m, 1 H) 5.90 (s, 2 H) 6.73 (d, J=7.93 Hz, 1 H)
7.01 (d, J=8.03 Hz, 1 H) 7.27 (s, 1 H) 8.11 (s, 1 H)
O
H
OMe
O
O
O
methyl 5-formylbenzo[d][1,3]dioxole-4-carboxylate (135)65, 69a
136
n-BuLi (1M in hexanes) (0.5 mL, 0.4756 mmol) was added dropwise over 10 minutes to
a stirred and cooled solution (-78°C) of 1-(benzo[d][1,3]dioxol-5-yl)-Ncyclohexylmethanimine (100 mg, 0.4324 mmol), TMEDA (55 mg, 0.4756 mmol) in THF
(3.5 mL). The temperature was then raised to -20°C and stirred for 15 minutes. The
temperature was cooled back down to -78°C and methyl chloroformate (0.67 mL, 0.8648
mmol) was added dropwise over 10 minutes, and then the cold bath was removed. Once
the reaction mixture reached room temperature, 15% HCl (0.35 mL) was added. Stirring
was continued for one hour and then the solution was concentrated. The residue was
extracted with diethyl ether (2 x 10 mL). The combined organic extracts were washed
with water (2 x 5 mL), saturated sodium bicarbonate (2 x 5 mL) and brine (5 mL) and
dried over sodium sulfate. It was then concentrated under reduced pressure. The residue
was purified by silica gel chromatography eluting with 25% ethyl acetate in hexanes to
give methyl 5-formylbenzo[d][1,3]dioxole-4-carboxylate (13 mg, 14%). 1H NMR (300
MHz, CHLOROFORM-d) δ ppm 3.87 (s, 3 H) 6.01 (s, 2 H) 7.19 (s, 1 H) 7.35 (d, J=7.84
Hz, 1 H) 9.75 (s, 1 H).
O
OH
1H-indene-3-carboxylic acid (142)72
To a solution of indene (50 mg, 0.43 mmol) in dry THF (2 mL) at -78°C was added nBuLi (1M in hexanes) (0.47 mL, 0.47 mmol) over a period of 20 minutes under a
nitrogen atmosphere. After being stirred at -78°C for 20 minutes, solid CO2 was added
137
and the mixture stirred for another 20 minutes. The reaction mixture was acidified with
10% HCl and the solvent evaporated. To the residue was added 5% HCl, and the aqueous
layer was extracted with ethyl acetate. The organic layer was washed with brine and dried
over magnesium sulfate. The solvent was evaporated and the residue was treated with
hexane to give a solid. The solid was filtered, washed with hexane and dried under
reduced pressure to give 1H-indene-3-carboxylic acid (45 mg, 65%) as a yellow
crystalline solid that was used without further purification. 1H NMR (300 MHz,
CHLOROFORM-d) δ ppm 3.62 (s, 2 H) 7.33 (d, J=7.27 Hz, 1 H) 7.37 - 7.46 (m, 1 H)
7.53 (d, J=7.46 Hz, 1 H) 7.66 (s, 1 H) 8.11 (d, J=7.46 Hz, 1 H) (Missing one
exchangeable proton).
O
O
O
3-oxobutyl 1H-indene-3-carboxylate (145)75
4-hydroxy-2-butanone (38 mg, 0.429 mmol) and triethylamine (87 mg, 0.858 mmol)
were dissolved in dry dichloromethane (3 mL) and stirred at 0°C for 2 hours. Afterwards,
1H-indene-3-carbonyl chloride (115 mg, 0.644 mmol) was dissolved in dry
dichloromethane and the solution was added to the mixture. The mixture was allowed to
stir overnight under nitrogen. The reaction mixture was washed with saturated
ammonium chloride, saturated sodium bicarbonate and then water. The combined organic
layers were dried over magnesium sulfate and the solvent was removed in vacuo. The
residue was purified by silica gel chromatography eluting with 75% petroleum ether in
138
ethyl acetate to give 3-oxobutyl 1H-indene-3-carboxylate (102 mg, 69%). 1H NMR (300
MHz, CHLOROFORM-d) δ ppm 2.17 (s, 3 H) 2.85 (t, J=6.28 Hz, 2 H) 4.52 (t, J=6.28
Hz, 2 H) 7.22 (br. s., 2 H) 7.24 - 7.33 (m, 2 H) 7.35 - 7.44 (m, 2 H) 7.92 (d, J=7.46 Hz, 1
H)
O
O
O
3-oxobutyl 1H-indene-3-carboxylate (145)74
1H-indene-3-carboxylic acid (100 mg, 0.624 mmol) was placed in a round-bottomed
flask along with 4-hydroxybutan-2-one (61 mg, 0.687 mmol) and 10 mol% sulfuric acid
in dry THF (5 mL). The mixture was heated to reflux for 2 days. The mixture was diluted
with ethyl acetate and washed with saturated aqueous sodium bicarbonate, water and
brine. The combined organic layers were dried over magnesium sulfate and concentrated
in vacuo. The residue was purified by silica gel chromatography eluting with 30% ethyl
acetate in hexanes to give 3-oxobutyl 1H-indene-3-carboxylate (86 mg, 60%). 1H NMR
(300 MHz, CHLOROFORM-d) δ ppm 2.09 (s, 3 H) 3.56 (s, 2 H) 4.17 (t, J=5.90 Hz, 2 H)
4.38 (t, J=5.95 Hz, 2 H) 7.31 - 7.43 (m, 2 H) 7.47 - 7.55 (m, 2 H) 8.06 (d, J=7.46 Hz, 1
H).
O
O
OH
3-oxobutanoic acid (148)76
139
To a solution of methyl 3-oxobutanoate (1 g, 8.62 mmol) in dichloromethane/methanol
(9:1) was added a methanolic solution of sodium hydroxide (3N) (4 eq). After 3 minutes
of stirring, the solution became cloudy and the sodium salt of the carboxylic acid began
to precipitate. The mixture was stirred until all of the ester was consumed to give a large
amount of the white precipitate. The solvents were removed under vacuum, and the
residue was diluted with water and the aqueous phase extracted with diethyl ether in
order to isolate the alcohol and any unreacted ester. The aqueous phase was then cooled,
acidified to pH 2 with dilute HCl and extracted with dichloromethane. The organic layers
were combined and dried over magnesium sulfate and the solvent was removed in vacuo
to provide 3-oxobutanoic acid (637 mg, 72%). The crude was used in further reactions.
1
H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.26 (s, 3 H) 3.49 (s, 2 H) (missing 1
exchangeable proton).
O
OTBS
4-((tert-butyldimethylsilyl)oxy)butan-2-one (161)84
4-hydroxybutan-2-one (100 mg, 1.13 mmol) was dissolved in dry dichloromethane (5
mL) with imidazole (231 mg, 3.39 mmol). The solution was cooled down to 0°C and tertbutyldimethylsilyl chloride (205 mg, 1.36 mmol) was added. The reaction was stirred for
2 hours. The reaction was quenched with water (5 mL). The aqueous layer was extracted
with dichloromethane (3 x 5 mL). The combined organic layers were washed with
saturated aqueous sodium bicarbonate, dried over magnesium sulfate and concentrated in
vacuo. The residue was purified by silica gel chromatography eluting with 10% ethyl
140
acetate in hexanes to give 4-((tert-butyldimethylsilyl)oxy)butan-2-one (213 mg, 82%). 1H
NMR (300 MHz, CHLOROFORM-d) δ ppm 0.00 (s, 6 H) 0.83 (s, 9 H) 2.12 (s, 3 H) 2.56
(t, J=6.23 Hz, 2 H) 3.83 (t, J=6.23 Hz, 2 H).
O
O
Hg
O
N2
O
N2
bis(1-diazo-2-ethoxy-2-oxoethyl)mercury (175)88
Yellow mercuric oxide (100 mg, 0.462 mmol) was added over a period of 4 hours to
ethyldiazoacetate (105 mg, 0.923 mmol) in diethyl ether at -10°C with vigorous stirring.
After the yellow mercuric oxide was dissolved, magnesium sulfate (72 mg, 0.598 mmol)
and diethyl ether (1 mL) were added to the reaction mixture. The mixture was slowly
warmed to 0°C and maintained at 0°C for 20 hours. At this time, diethyl ether (1 mL) was
added and the solid was filtered and washed with diethyl ether. The solvent was
evaporated under reduced pressure to give bis(1-diazo-2-ethoxy-2-oxoethyl)mercury (98
mg, 50%) as a yellow solid. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.30 (t,
J=7.18 Hz, 6 H) 4.24 (q, J=7.11 Hz, 4 H).
O
O
Br
O
N2
ethyl 4-bromo-2-diazo-3-oxobutanoate (177)88
To a solution containing bis(1-diazo-2-ethoxy-2-oxoethyl)mercury (500 mg, 1.17 mmol)
in dichloromethane (10 mL) under nitrogen at 0°C was added dropwise bromoacetyl
141
bromide (497 mg, 2.46 mmol) with vigorous stirring. After warming to room
temperature, the mixture was stirred for an additional 30 minutes. The mercuric salts
formed were decanted and the mixture was filtered through a plug of silica using diethyl
ether as the eluent. The filtrate was concentrated under reduced pressure and the residue
was purified by silica gel chromatography eluting with 60% ethyl acetate in hexanes to
give ethyl 4-bromo-2-diazo-3-oxobutanoate (189 mg, 69%). 1H NMR (300 MHz,
CHLOROFORM-d) δ ppm 1.25 (t, J=7.18 Hz, 3 H) 3.89 (s, 2 H) 4.12 (q, J=7.14 Hz, 2
H).
S
N
O
O
2-(benzofuran-2-yl)-1-morpholinoethane-1-thione (197)93
2-benzofuranylmethyl ketone (3.0 g, 18.7 mmol), morpholine (2.45 g, 28.1 mmol) and
sulfur (6.59 mg, 20.6 mmol) were placed in a round-bottomed flask. The flask was heated
to 80°C overnight. After cooling, methanol was added and the solid was collected via
filtration to give 2-(benzofuran-2-yl)-1-morpholinoethane-1-thione (3.5 g, 72%). The
solid product did not need purification. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm
2.88 - 2.99 (m, 2 H) 3.78 - 3.85 (m, 2 H) 3.87 - 3.97 (m, 2 H) 4.36 - 4.44 (m, 2 H) 4.49 (s,
2 H) 6.67 (s, 1 H) 7.20 - 7.27 (m, 2 H) 7.44 (d, J=7.55 Hz, 1 H) 7.54 (d, J=7.08 Hz, 1 H).
O
OH
O
142
2-(benzofuran-2-yl)acetic acid (198)93
2-(benzofuran-2-yl)-1-morpholinoethane-1-thione (500 mg, 1.91 mmol) was dissolved in
concentrated HCl and concentrated acetic acid. The solution was stirred at 80°C for 18
hours. The reaction was monitored by TLC. The solvent was evaporated in vacuo. The
product was stirred in cold 1N HCl. The solid was filtered and washed with cold 1N HCl.
The brown filter cake was purified by silica gel chromatography eluting with a gradient
of 0-10% methanol in dichloromethane. Fractions were combined and concentrated to
give 2-(benzofuran-2-yl)acetic acid (321 mg, 95%). 1HNMR shows the necessary peaks.
1
H NMR (300 MHz, Acetone) δ ppm 3.70 - 3.72 (m, 2 H) 6.74 - 6.78 (m, 1 H) 6.87 - 6.94
(m, 1 H) 7.00 - 7.06 (m, 1 H) 7.44 - 7.50 (m, 1 H) 7.56 - 7.63 (m, 1 H).
O
O
O
methyl 2-(benzofuran-2-yl)acetate (199)93
2-(benzofuran-2-yl)acetic acid (500 mg, 2.84 mmol) was dissolved in methanol (17 mL)
and concentrated sulfuric acid (3.3 mL). The mixture, which was originally a suspension,
was stirred at reflux for 2 hours. A mixture consisting of water (3.3 mL), potassium
hydroxide (0.11 g) and ethyl acetate (2 mL) was added. After mixing well, the organic
layer was allowed to separate and was isolated. The aqueous layer was extracted with
ethyl acetate and the combined organic extracts were dried over sodium sulfate, filtered,
and evaporated. The residue was purified by silica gel chromatography eluting with 40%
ethyl acetate in hexanes to give methyl 2-(benzofuran-2-yl)acetate (150 mg, 28%). 1H
143
NMR (300 MHz, DMSO-d6) δ ppm 3.33 (s, 2 H) 3.67 (s, 3 H) 6.79 (s, 1 H) 7.19 - 7.31
(m, 2 H) 7.53 (d, J=7.74 Hz, 1 H) 7.59 (d, J=7.08 Hz, 1 H).
OH
OH
2-(1-hydroxyprop-2-yn-1-yl)phenol (202)95
Salicylaldehyde (3 g, 24.57 mmol) in dry THF (30 mL) was slowly added to a solution of
ethynyl magnesium bromide (0.5 M in THF) (64 mL) at room temperature. This resulted
in an exothermic reaction. After the reaction subsided, THF (30 mL) was added and the
mixture was allowed to stir overnight at room temperature. The reaction was quenched
with 1N HCl and filtered through Celite. Brine was added and extracted with ethyl
acetate (3 x 25 mL) and dichloromethane (3 x 25 mL), dried over magnesium sulfate and
concentrated. The residue was purified by silica gel chromatography eluting with 25%
ethyl acetate in hexanes to give 2-(1-hydroxyprop-2-yn-1-yl)phenol (0.74 g, 20%). 1H
NMR (300 MHz, CHLOROFORM-d) δ ppm 3.61 (s, 1 H) 5.82 - 5.90 (m, 1 H) 6.94 (s, 1
H) 7.37 - 7.43 (m, 1 H) 7.67 - 7.75 (m, 1 H) 7.77 - 7.85 (m, 1 H) (missing two
exchangeable protons).
Br
OTBS
(4-bromobutoxy)(tert-butyl)dimethylsilane (205)84
4-bromobutanol (1 g, 6.5 mmol) in acetonitrile (20 mL) was placed in a round-bottomed
flask and triethylamine (2.26 mL, 13 mmol) was added. The mixture was cooled to 0°C
144
and tert-butyldimethylsilyl chloride (2.46 g, 16.3 mmol) was added and the mixture was
allowed to warm to room temperature and stir overnight. Dichloromethane was added
and the organic layers were washed with saturated aqueous sodium bicarbonate, water
and brine. The combined organic layers were dried over magnesium sulfate and
concentrated in vacuo. The residue was purified by silica gel chromatography eluting
with 10% ethyl acetate in hexanes to give (4-bromobutoxy)(tert-butyl)dimethylsilane
(1.37 g, 78%). 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.00 (s, 6 H) 0.82 (s, 9 H)
1.50 - 1.62 (m, 2 H) 1.69 - 1.88 (m, 2 H) 3.30 - 3.50 (m, 2 H) 3.55 (t, J=6.23 Hz, 2 H).
O
OH
tetrahydro-2H-pyran-2-ol (210)98a
An aqueous solution of cooled 1N HCl was added to a cooled (0°C) stirred sample of 2,3dihydropyran (5 g, 59.44 mmol). The mixture was stirred at 0°C for 15 minutes before
being warmed to room temperature and stirred for 1 hour. The mixture was then extracted
with dichloromethane and the combined organic layers were washed with saturated
aqueous sodium bicarbonate, water, brine, dried over magnesium sulfate and evaporated
to give tetrahydro-2H-pyran-2-ol (2.04 g, 34%) as a pale yellow oil. The crude residue
was not purified further. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.66 - 1.95 (m,
6 H) 3.87 (ddd, J=10.79, 7.06, 3.49 Hz, 2 H) 5.30 (s, 1 H).
OH
HO
145
hept-6-ene-1,5-diol (211)97a
tetrahydro-2H-pyran-2-ol (4.492 g, 43.98 mmol) in dry THF (45 mL) was slowly added
to a solution of vinyl magnesium bromide (1M in THF) (53 mL) at room temperature.
This resulted in an exothermic reaction, which upon cooling resulted in the solidification
of the reaction mixture. This was then treated further with dry THF (45 mL) and the
suspension stirred vigorously for 16 hours. The reaction was quenched with 1N HCl and
was filtered through Celite. Brine was added and the solution was extracted with ethyl
acetate (3 x 25 mL) and dichloromethane (3 x 25 mL), dried over magnesium sulfate and
concentrated to give an oil. The product was purified by silica gel chromatography
eluting with 60% ethyl acetate in petroleum ether to give hept-6-ene-1,5-diol (2.943 g,
51%). Product was visualized with potassium permanganate stain. 1H NMR (300 MHz,
CHLOROFORM-d) δ ppm 1.54 - 1.70 (m, 6 H) 3.42 - 3.54 (m, 2 H) 3.98 - 4.14 (m, 1 H)
5.51 - 5.68 (m, 2 H) 5.82 (dd, J=10.39, 6.70 Hz, 1 H) (missing two exchangeable
protons).
OH
TBSO
7-((tert-butyldimethylsilyl)oxy)hept-1-en-3-ol (212)84
hept-6-ene-1,5-diol (2.943 g, 22.61 mmol) was dissolved in DMF (36 mL) and was
treated with imidazole (1.85 g, 27.13 mmol), followed by TBSCl (3.41 g, 22.61 mmol) at
-5°C. After stirring overnight, diethyl ether (70 mL) and water (70 mL) were added. The
organic layer was separated and the aqueous layer was further extracted with diethyl
ether. The organic layers were washed with a 5% lithium chloride solution to remove
146
DMF. After drying over magnesium sulfate, and evaporation of the solvent, the residue
was purified by silica gel chromatography eluting with 12% diethyl ether in petroleum
ether to give 7-((tert-butyldimethylsilyl)oxy)hept-1-en-3-ol (2.182 g, 40%). 1H NMR
(300 MHz, CHLOROFORM-d) δ ppm 0.06 (s, 6 H) 0.88 (s, 9 H) 1.55 - 1.69 (m, 6 H)
3.42 - 3.54 (m, 2 H) 5.51 - 5.67 (m, 2 H) 5.77 - 5.91 (m, 1 H) (Missing one exchangeable
proton).
OH
TBDPSO
7-((tert-butyldiphenylsilyl)oxy)hept-1-en-3-ol (212a)84
hept-6-ene-1,5-diol (3.732 g, 28.67 mmol) was dissolved in DMF (40 mL) and was
treated with imidazole (2.34 g, 34.4 mmol) followed by TBDPSCl (7.88 g, 28.67 mmol)
at -5°C. After stirring overnight, diethyl ether (75 mL) and water (75 mL) were added.
The organic layer was separated and the aqueous layer further extracted with diethyl
ether. The combined organic layers were washed with a 5% lithium chloride solution to
remove DMF. After drying over magnesium sulfate and evaporation of the solvent, the
residue was purified by silica gel chromatography eluting with 10% diethyl ether in
petroleum ether to give 7-((tert-butyldiphenylsilyl)oxy)hept-1-en-3-ol (3.74 g, 35%). 1H
NMR (300 MHz, CHLOROFORM-d) δ ppm 0.95 (s, 9 H) 1.47 - 1.61 (m, 6 H) 3.32 3.46 (m, 2 H) 3.87 - 4.03 (m, 1 H) 5.42 - 5.59 (m, 2 H) 5.67 - 5.84 (m, 1 H) 7.22 - 7.36
(m, 5 H) 7.60 (dd, J=7.13, 1.37 Hz, 5 H) (missing one exchangeable proton).
147
O
HO
N
OMe
5-hydroxy-N-methoxy-N-methylpentanamide (214)99
δ-valerolactone (2 g, 19.98 mmol) was dissolved in dry benzene (80 mL) and
trimethylaluminum (2M in toluene) (30 mL) was added at -10°C. N,Odimethylhydroxylamine (2.92 g, 29.96 mmol) was then added and the reaction was
allowed to stir for 30 minutes. Isopropanol was slowly added to the cold solution to
quench the remaining trimethylaluminum. Dichloromethane was added and the organic
layer was separated. The combined organic layers were washed with saturated aqueous
sodium bicarbonate, water, brine and dried over magnesium sulfate. The solvent was
removed in vacuo The residue was purified by silica gel chromatography eluting with
75% ethyl acetate in hexanes to give 5-hydroxy-N-methoxy-N-methylpentanamide (314
mg, 10%). 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.56 - 1.67 (m, 2 H) 1.68 1.80 (m, 2 H) 2.47 (t, J=6.85 Hz, 2 H) 3.18 (s, 3 H) 3.64 (t, J=6.18 Hz, 2 H) 3.68 (s, 3 H)
(missing one exchangeable proton).
Br
OH
2-(2-bromophenyl)ethan-1-ol (219)77
Lithium aluminum hydride (LAH) (89 mg, 2.35 mmol) was placed in a round-bottomed
flask along with dry THF (20 mL). A reflux condenser was placed on the round-bottomed
flask and a nitrogen line used. The slurry was cooled in an ice bath and a solution of
148
methyl 2-(2-bromophenyl)acetate (500 mgs, 1.96 mmol) in dry THF (20 mL) was added
with stirring. The ice bath was removed and the mixture was refluxed for 3 days. The
mixture was then cooled in an ice bath and excess LAH was decomposed by the addition
of water (2 mL), 15% sodium hydroxide (2 mL) and water (6 mL). After stirring for
another 20 minutes, the mixture was filtered with suction and the precipitate was washed
with ether. The combined organic extracts were washed with water, brine and saturated
sodium bicarbonate and dried over sodium sulfate and concentrated in vacuo. The residue
was purified by silica gel chromatography eluting with 10% ethyl acetate in hexanes to
give 2-(2-bromophenyl)ethan-1-ol (85 mg, 22%). 1H NMR (300 MHz,
CHLOROFORM-d) δ ppm 1.55 (br. s., 1 H) 3.06 (t, J=6.70 Hz, 2 H) 3.91 (t, J=6.61 Hz,
2 H) 7.04 - 7.18 (m, 1 H) 7.21 - 7.40 (m, 2 H) 7.58 (d, J=7.93 Hz, 1 H).
Br
OTBS
(2-bromophenethoxy)(tert-butyl)dimethylsilane (220)84
2-(2-bromophenyl)ethan-1-ol (2.082 g, 10.36 mmol) was dissolved in DMF (100 mL)
and treated with imidazole (846 mgs, 12.43 mmol) followed by TBSCl (1.56 g, 10.36
mmol) at -5°C. After stirring overnight, ether (100 mL) and water (100 mL) were added.
The organic layer was separated and the aqueous layer further extracted with ether. The
organic layers were washed with 5% lithium chloride to remove DMF. After drying over
sodium sulfate and evaporation of the solvent, the residue was purified by silica gel
chromatography eluting with a gradient of 10-30% ethyl acetate in hexanes to give (2-
149
bromophenethoxy)(tert-butyl)dimethylsilane (1.057 g, 34%). 1H NMR (300 MHz,
CHLOROFORM-d) δ ppm 0.00 (s, 6 H) 0.89 (s, 9 H) 3.00 (t, J=6.99 Hz, 2 H) 3.79 - 3.92
(m, 2 H) 7.02 - 7.15 (m, 1 H) 7.18 - 7.36 (m, 2 H) 7.54 (d, J=7.93 Hz, 1 H).
OH
Br
1-bromooct-7-en-2-ol (222a)101
Dibromoborane dimethyl sulfide (4.4 mL, 4.4 mmol) was slowly added to a stirred
solution of DCM and 1-bromooct-7-en-2-ol (1.0 g, 7.9 mmol) at room temperature under
a nitrogen atmosphere. After 15 minutes, the intermediate dialkylborane was treated with
water and the resulting bromohydrins were extracted with DCM, dried over magnesium
sulfate and concentrated to give 1-bromooct-7-en-2-ol. The crude product was carried
forward in other reactions. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.30 - 1.51
(m, 4 H) 1.54 - 1.66 (m, 2 H) 1.97 - 2.15 (m, 2 H) 2.21 (br. s., 1 H) 3.32 - 3.48 (m, 1 H)
3.50 - 3.62 (m, 1 H) 3.67 - 3.91 (m, 1 H) 4.86 - 5.12 (m, 2 H) 5.81 (ddt, J=17.02, 10.22,
6.68, 6.68 Hz, 1 H).
OMOM
Br
8-bromo-7-(methoxymethoxy)oct-1-ene (222)102
1-bromooct-7-en-2-ol (1.0 g, 4.83 mmol) was dissolved in DCM and triethylamine (0.74
mL, 5.313 mmol) was added. After stirring at room temperature for 30 minutes, MOMCl
(389 mgs, 4.83 mmol) was added and the mixture allowed to stir for 8 hours. The
150
reaction was quenched with water and the product extracted with DCM. The combined
organic extracts were washed with brine, dried over sodium sulfate and concentrated in
vacuo to give 8-bromo-7-(methoxymethoxy)oct-1-ene (982 mgs, 81%). The crude
product was carried forward for further reactions. 1H NMR (300 MHz, CHLOROFORMd) δ ppm 1.35 (br. s., 4 H) 1.47 - 1.70 (m, 3 H) 2.05 (d, J=6.04 Hz, 1 H) 3.30 - 3.41 (m, 4
H) 3.41 - 3.53 (m, 2 H) 3.64 - 3.83 (m, 1 H) 4.55 - 4.62 (m, 1 H) 4.63 - 4.76 (m, 1 H)
4.88 - 5.05 (m, 1 H) 5.67 - 5.88 (m, 1 H).
O
H
O
O
O
methyl (E)-3-(2-formylphenoxy)acrylate (226)105
N-methylmorpholine (248 mgs, 2.45 mmol) was added to a mixture of salicylaldehyde (5
g, 40.94 mmol), methyl propiolate (4.13 g, 49.13 mmol) and MeCN (50 mL). The solvent
was removed after stirring overnight at room temperature to give methyl (E)-3-(2formylphenoxy)acrylate (8.17 g, 97%). The crude product was carried forward. 1H NMR
(300 MHz, CHLOROFORM-d) δ ppm 3.72 - 3.81 (m, 3 H) 5.67 (d, J=12.27 Hz, 1 H)
7.17 (d, J=8.31 Hz, 1 H) 7.34 (t, J=7.55 Hz, 1 H) 7.59 - 7.71 (m, 1 H) 7.87 (d, J=12.28
Hz, 1 H) 7.95 (dd, J=7.74, 1.51 Hz, 1 H) 10.39 (s, 1 H).
O
O
O
O
methyl 2-(3-oxo-2,3-dihydrobenzofuran-2-yl)acetate (228)106
151
A mixture of methyl (E)-3-(2-formylphenoxy)acrylate (1 g, 4.85 mmol), thiazolium
chloride (131 mgs, 0.485 mmol) and DMF (10 mL) was evacuated and flushed with
nitrogen and heated near reflux overnight. Toluene (100 mL) was added and the solution
was washed with 5% ammonium hydroxide. The solution was separated and dried over
sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel
chromatography eluting with 30% ethyl acetate in hexanes to give methyl 2-(3-oxo-2,3dihydrobenzofuran-2-yl)acetate (420 mgs, 42%). 1H NMR (300 MHz, CHLOROFORMd) δ ppm 2.74 (dd, J=17.09, 8.03 Hz, 1 H) 3.02 (dd, J=17.00, 3.59 Hz, 1 H) 3.60 - 3.67
(m, 3 H) 4.83 (dd, J=8.12, 3.59 Hz, 1 H) 6.99 - 7.11 (m, 2 H) 7.51 - 7.68 (m, 2 H).
O
S
O
S
O
O
5-(1,3-dithian-2-yl)-2,2,2',2'-tetramethyl-4,4'-bi(1,3-dioxolane) (234)110
To a solution of L-arabinose (2g, 13.32 mmol) in 35% HCl (4 mL) was added propane
1,3-dithiol (1.28 mL, 12.7 mmol). The solution was stirred overnight at room temperature
and then the mixture was poured into acetone (40 mL) at 0°C. After stirring at room
temperature for 2 hours, the mixture was cooled to 0°C and 28% ammonium hydroxide
(5 mL) was slowly added. The precipitate was removed by filtration and the filtrate
concentrated. The residue was taken up with DCM/water (1:2, 30 mL) and the aqueous
layer extracted with DCM (3 x 10 mL). The combined organic extracts were dried over
magnesium sulfate, filtered and concentrated. The residue was purified by silica gel
152
chromatography eluting with 50% ethyl acetate in dichloromethane to give 5-(1,3dithian-2-yl)-2,2,2',2'-tetramethyl-4,4'-bi(1,3-dioxolane) (1.77 g, 41%). 1H NMR (300
MHz, CHLOROFORM-d) δ ppm 1.36 (s, 3 H) 1.41 (s, 3 H) 1.46 (s, 3 H) 1.49 (s, 3 H)
2.08 (br. s., 2 H) 2.68 - 2.93 (m, 2 H) 3.04 (br. s., 2 H) 3.99 - 4.30 (m, 6 H).
O
O HO
O
OMe
O
O
methyl 2-hydroxy-2-(2,2,2',2'-tetramethyl-[4,4'-bi(1,3-dioxolan)]-5-yl)acetate
(236)115a
p-toluenesulfonic acid (30 mg, 0.16 mmol) was added to a stirred suspension of
gluconolactone (2 g, 11.16 mmol) in a mixture of 2,2-dimethoxypropane (3.4 g, 32.64
mmol), acetone (1.2 mL) and methanol (0.4 mL). The reaction was stirred under nitrogen
for 4 days. Sodium bicarbonate (0.2 g) was added and the reaction mixture was stirred for
1 hour, then filtered through Celite. The solvent was removed in vacuo and the residue
taken up with DCM (10 mL) and washed with water (1 mL). The aqueous phase was
extracted with DCM (8 mL) and the combined organic extracts were dried over
magnesium sulfate, filtered and concentrated. The residue was purified by silica gel
chromatography eluting with 15% ethyl acetate in hexanes to give methyl 2-hydroxy-2(2,2,2',2'-tetramethyl-[4,4'-bi(1,3-dioxolan)]-5-yl)acetate (2.01 g, 62%). 1H NMR (300
MHz, CHLOROFORM-d) δ ppm 1.32 (s, 3 H) 1.34 (s, 3 H) 1.37 (s, 3 H) 1.40 (s, 3 H)
153
3.81 (s, 3 H) 3.93 - 4.16 (m, 4 H) 4.21 (d, J=7.27 Hz, 1 H) 4.29 - 4.36 (m, 1 H) (missing
one exchangeable proton).
O
O HO
O
OH
O
1-(2,2,2',2'-tetramethyl-[4,4'-bi(1,3-dioxolan)]-5-yl)ethane-1,2-diol (237)115a
To a stirred suspension of lithium aluminum hydride (LAH) (1.03 g, 27.14 mmol) in
diethyl ether was added methyl 2-hydroxy-2-(2,2,2',2'-tetramethyl-[4,4'-bi(1,3dioxolan)]-5-yl)acetate (3.17 g, 11 mmol) dropwise at room temperature. The reaction
mixture was heated to reflux overnight. The reaction mixture was cooled to 0°C and
quenched with water (2 mL), 15% NaOH (2 mL), water (4 mL) and stirred for 1 hour at
0°C. The mixture was extracted with diethyl ether (3 x 10 mL). The combined organic
layers were washed with brine, dried over magnesium sulfate, filtered and concentrated in
vacuo. The residue was purified by silica gel chromatography eluting with 75% ethyl
acetate in hexanes to give 1-(2,2,2',2'-tetramethyl-[4,4'-bi(1,3-dioxolan)]-5-yl)ethane-1,2diol (1.07 g, 37%). 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.28 (s, 3 H) 1.32 (s,
3 H) 1.35 (s, 3 H) 1.36 (br. s., 3 H) 3.66 - 3.76 (m, 2 H) 3.86 - 4.13 (m, 6 H) (missing two
exchangeable protons).
154
O
O HO
O
O
O
2-hydroxy-2-(2,2,2',2'-tetramethyl-[4,4'-bi(1,3-dioxolan)]-5-yl)acetaldehyde (230)115b
1-(2,2,2',2'-tetramethyl-[4,4'-bi(1,3-dioxolan)]-5-yl)ethane-1,2-diol (940 mg, 4.35 mmol)
and sodium periodate (930 mg, 4.35 mmol) were placed in a round-bottomed flask with
DCM (15 mL). The reaction was refluxed overnight. The next morning, sodium
bicarbonate (0.5 g) was added. The solution was cooled and washed with water, saturated
aqueous sodium bicarbonate, and brine. The combined organic layers were dried over
magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica
gel chromatography eluting with 25% ethyl acetate in hexanes to give 2-hydroxy-2(2,2,2',2'-tetramethyl-[4,4'-bi(1,3-dioxolan)]-5-yl)acetaldehyde (15 mg, 1.6%). 1H NMR
(300 MHz, CHLOROFORM-d) δ ppm 1.28 (s, 3 H) 1.32 (s, 3 H) 1.35 (s, 3 H) 1.36 (s, 3
H) 3.67 - 3.77 (m, 2 H) 3.86 - 4.13 (m, 4 H) 7.53 - 18.21 (m, 0 H) 9.68 - 9.70 (m, 1 H)
(missing one exchangeable proton).
O
NH
1,5-dihydro-2H-pyrrol-2-one (239)116a
Pyrrole (3 g, 44.7 mmol) was dissolved in water (150 mL) and was refluxed in a roundbottomed flask with 30% hydrogen peroxide (6 g) and barium carbonate (0.9 g, 4.6
mmol) for 4 hours. Afterwards, excess oxidant was quenched by addition of lead (IV)
155
dioxide to the boiling solution. The solution was filtered and evaporated under reduced
pressure avoiding heating above 50°C, until it reached a syrupy consistency. After
treatment with dioxane and filtration, the filtrate was evaporated under reduced pressure.
The residue was purified by silica gel chromatography eluting with 30% ethyl acetate in
hexanes to give 1,5-dihydro-2H-pyrrol-2-one (1.37 g, 37%). 1H NMR (300 MHz,
CHLOROFORM-d) δ ppm 3.57 - 3.75 (m, 2 H) 6.15 (d, J=16.24 Hz, 1 H) 7.15 (d,
J=16.05 Hz, 1 H) 7.35 (br. s., 1 H).
O
NBoc
tert-butyl 2-oxo-2,5-dihydro-1H-pyrrole-1-carboxylate (240)116
60% sodium hydride (200 mg, 5.22 mmol) was placed in a round-bottomed flask along
with dry hexanes (20 mL) under a nitrogen atmosphere. The mixture was stirred for 10
seconds, allowed to settle and the hexanes was removed. (repeat 2 more times). Dry THF
(20 mL) and 1,5-dihydro-2H-pyrrol-2-one (400 mg, 4.8 mmol) were added to the flask.
The reaction mixture was stirred at room temperature for 1 hour. Di-tert-butyldicarbonate
(1.571 g, 7.2 mmol) was added and the mixture was allowed to stir overnight. The
solution was quenched with brine and extracted with THF. The combined organic
extracts were dried over magnesium sulfate, filtered and concentrated. The residue was
purified by silica gel chromatography eluting with 10% ethyl acetate in hexanes to give
tert-butyl 2-oxo-2,5-dihydro-1H-pyrrole-1-carboxylate (37 mg, 4.2%). 1H NMR (300
156
MHz, CHLOROFORM-d) δ ppm 1.58 (s, 9 H) 3.50 - 3.52 (m, 2 H) 7.34 - 7.36 (m, 1 H)
(missing one buried proton).
TBSO
Boc
N
tert-butyl 2-((tert-butyldimethylsilyl)oxy)-1H-pyrrole-1-carboxylate (231)116a
To a solution of tert-butyl 2-oxo-2,5-dihydro-1H-pyrrole-1-carboxylate (350 mg, 1.91
mmol) in DCM (2 mL) was added 2,6-lutidine (0.6125 g, 5.72 mmol) and tertButyldimethylsilyl trifluoromethane (0.56 g, 2.11 mmol) under nitrogen at room
temperature. After the reaction stirred for 1 day, the solvent was removed in vacuo. The
residue was purified by silica gel chromatography eluting with 50% ethyl acetate in
benzene to give tert-butyl 2-((tert-butyldimethylsilyl)oxy)-1H-pyrrole-1-carboxylate (13
mg, 2.3%). 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.00 (s, 6 H) 0.78 (s, 9 H)
0.82 (s, 9 H) 7.06 (s, 1 H) 7.09 (s, 1 H) 7.64 (t, J=7.74 Hz, 1 H).
O
TsHN
N
OH
2-(2-tosylhydrazono)acetic acid (244)118
A solution of glyoxylic acid (50% in water) (6 mL) in water (54 mL) was placed in a
round-bottomed flask and warmed in a steam bath to 60°C. This solution was then treated
with a warm solution of p-toluenesulfonylhydrazide (10 g, 53.69 mmol) in 2M HCl (30
mL). The resulting mixture was heated in a steam bath with continuous stirring until all
of the hydrazine, which was an oil, solidified. The reaction mixture was allowed to cool
157
to room temperature and then put in the refrigerator overnight. The solid was filtered,
washed with cold water and allowed to dry for 2 days. The solid was dissolved in boiling
ethyl acetate (50 mL), filtered and then carbon tetrachloride (100 mL) was added and the
solution was allowed to cool. The solid was allowed to cool in the refrigerator overnight.
The solid was collected and washed with a cold mixture of ethyl acetate and carbon
tetrachloride (1:2 by volume). After drying, 2-(2-tosylhydrazono)acetic acid (9.74 g,
75%) was collected as a white crystalline solid. 1H NMR (300 MHz, CHLOROFORM-d)
δ ppm 2.44 (s, 3 H) 7.32 (s, 1 H) 7.44 (d, J=8.03 Hz, 2 H) 7.82 (d, J=8.12 Hz, 2 H)
(missing two exchangeable protons).
O
N O
O
O
N2
H
2,5-dioxopyrrolidin-1-yl 2-diazoacetate (247)119
To a suspension of 2-(2-tosylhydrazono)acetic acid (500 mg, 2.06 mmol) in dry benzene
was added thionyl chloride (0.3 mL, 4.13 mmol). The reaction mixture was heated to
reflux with stirring for 2 hours. The reaction mixture was cooled immediately and the
solvent removed in vacuo. The crude product was used for the next step. The acid
chloride was dissolved in dry DCM and was added over 30 minutes to a stirred
suspension of N-hydroxysuccinimide (261 mg, 2.27 mmol) and potassium carbonate (427
mg, 3.09 mmol) in dry DCM and maintained at 0°C. The resulting mixture was stirred at
0°C for 1 hour and then was warmed to room temperature and let stir for 3 hours. It was
then filtered through Celite and the filtrate concentrated in vacuo to give 2,5-
158
dioxopyrrolidin-1-yl 2-diazoacetate (145 mg, 38%). 1H NMR (300 MHz,
CHLOROFORM-d) δ ppm 2.80 - 2.84 (m, 4 H) 5.14 (br. s., 1 H).
O
N
TsHN
N
N'-(2-(azetidin-1-yl)-2-oxoethylidene)-4-methylbenzenesulfonohydrazide (248)120
A dry round-bottomed flask was charged with 2-(2-tosylhydrazono)acetic acid (100 mg,
0.413 mmol), azetidine HCl (39 mg, 0.413 mmol) and DCM (1 mL) under a nitrogen
atmosphere. After cooling to 0°C, a solution of N,N'-Dicyclohexylcarbodiimide (DCC)
(98 mg, 0.475 mmol) in DCM (1 mL) was added and the reaction was allowed to warm
to room temperature while stirring overnight. The mixture was filtered through Celite,
concentrated and purified by silica gel chromatography eluting with 50% ethyl acetate in
hexanes to give N'-(2-(azetidin-1-yl)-2-oxoethylidene)-4-methylbenzenesulfonohydrazide
(14 mg, 12%). 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.38 (t, J=7.84 Hz, 2 H)
2.44 (s, 3 H) 4.13 (t, J=7.60 Hz, 2 H) 4.33 (t, J=7.79 Hz, 2 H) 6.74 (s, 1 H) 7.32 (d,
J=8.21 Hz, 2 H) 7.83 (d, J=8.12 Hz, 2 H).
O
O
O
N
methyl 3-(azetidin-1-yl)-3-oxopropanoate (250)121
methyl-3-chloro-3-oxopropanoate (500 mg, 3.66 mmol) was dissolved in dry DCM and
was added over 30 minutes to a stirred suspension of azetidine HCl (209 mg, 3.66 mmol)
159
and potassium carbonate (1.26 g, 9.15 mmol) in dry DCM and maintained at 0°C. The
resulting mixture was stirred at 0°C for 1 hour and then let warm to room temperature
and let stir for 2 days. It was filtered, washed with DCM and the filtrate was concentrated
in vacuo. The residue was purified by silica gel chromatography eluting with 25% ethyl
acetate in hexanes to give methyl 3-(azetidin-1-yl)-3-oxopropanoate (498 mg, 86%). 1H
NMR (300 MHz, CHLOROFORM-d) δ ppm 2.26 - 2.38 (m, 2 H) 3.22 (s, 2 H) 3.77 (s, 3
H) 4.07 - 4.16 (m, 2 H) 4.22 (t, J=7.65 Hz, 2 H).
O
O
O
N
N2
methyl 3-(azetidin-1-yl)-2-diazo-3-oxopropanoate (251)52
triethylamine (0.2 mL, 1.431 mmol) was added to a solution of methyl 3-(azetidin-1-yl)3-oxopropanoate (75 mg, 0.477 mmol) and p-ABSA (172 mg, 0.715 mmol) in
acetonitrile (2 mL) at 0°C under nitrogen. The reaction was allowed to warm to room
temperature and stir overnight. The resulting suspension was filtered and washed with
acetonitrile. The filtrate was concentrated in vacuo to 1/3 the initial volume. The
remaining solution was diluted with diethyl ether and washed with water and brine. The
organic layer was dried over sodium sulfate and concentrated. The residue was purified
by silica gel chromatography eluting with 50% ethyl acetate in dichloromethane to give
methyl 3-(azetidin-1-yl)-2-diazo-3-oxopropanoate (35 mg, 45%). 1H NMR (300 MHz,
CHLOROFORM-d) δ ppm 2.29 (t, J=7.65 Hz, 2 H) 3.33 - 3.52 (m, 4 H) 3.79 (s, 3 H).
160
REFERENCES
1.
Seebach, D., Angew. Chem. Int. Ed. Engl. 1990, 29, 1320.
2.
Armstrong, R. W., J. Am. Chem. Soc. 1989, 111, 7530.
3.
The Lancet 2009, 374 (9685), 176.
4.
How long does it take for a new drug to go through clinical trials?
http://www.cancerresearchuk.org/cancer-help/about-cancer/cancerquestions/how-long-does-it-take-for-a-new-drug-to-go-through-clinical-trials long (accessed 8/12/14).
5.
Braun, M., Angew. Chem. Int. Ed. Engl. 1987, 99, 24.
6.
Maruoka, K., Angew. Chem. Int. Ed. Engl. 1985, 24, 668.
7.
Ireland, R. E., J. Am. Chem. Soc. 1976, 98, 2868.
8.
Blechert, S., Synthesis 1989, 71.
9.
Oppolzer, W., Angew. Chem. Int. Ed. Engl. 1977, 89, 10.
10.
Tramontini, M., Tetrahedron 1990, 46, 1791.
11.
Oare, D. A., J. Org. Chem. 1990, 55, 157.
12.
(a) Maryanoff, B. E., Chem. Rev. 1989, 89, 863; (b) Vedejs, E., J. Am. Chem. Soc.
1989, 111, 1519.
13.
Curran, D. P., Adv. Cycloaddit. 1988, 1, 129.
14.
Prodger, J. C., Tetrahedron 1989, 45, 7643.
15.
Narasimhan, N. S., Top. Curr. Chem 1987, 138, 63.
16.
(a) Seebach, D., Mod. Synth Methods 1983, 3, 217; (b) McMurry, J. E., Chem.
Rev. 1989, 89, 1513; (c) Pons, J. M., Tetrahedron 1988, 44, 4295.
161
17.
(a) Mitsunobu, O., Synthesis 1981, 1; (b) Varasi, M., J. Org. Chem. 1987, 52,
4235.
18.
Fabro, S.; Smith, R. L.; Williams, R. T., Nature 1967, 215, 296.
19.
Ariens, E. J., Eur. J. Clin. Pharmacol. 1984, 26, 663.
20.
Scott, J. W., Top. Stereochem. 1989, 19, 209.
21.
Hegstrom, R. A., Sci. Am. 1990, 262 (1), 98.
22.
Introduction to Heterocyclic Chemistry.
http://www.rsc.org/pdf/tct/heterosample.pdf (accessed August 15, 2014).
23.
Zuo, Z.; Li, W.; Manthiram, A., J. Mat. Chem. A 2013, 1, 10166.
24.
Xue, H.; Gao, Y.; Twamley, B.; Shreeve, J. M., Chem. Mat. 2005, (17), 191.
25.
(a) Padwa, A., J. Org. Chem. 1999, 64, 4079; (b) Enders, D., Synthesis 2004,
2980.
26.
(a) Rozwadowska, M., Heterocycles 1994, 39, 903; (b) Garcia-Moreno, M. I.,
Tetrahedron 2007, 63, 7879.
27.
Gentles, R., J. Chem. Soc. Perkin Trans. 1 1991, 6, 1423.
28.
Mehta, G.; Likhite, N. S., Tet. Lett. 2009, 50, 5263.
29.
(a) Li, X.; Ovaska, T., Org. Lett. 2007, 9, 3837-3840; (b) Masters, K.; Flynn, B.
L., Org. Biomol. Chem 2010, 8, 1290-1292; (c) Kerr, D.; Willis, A.; Flynn, B. L.,
Org. Lett. 2004, 6 (4), 457-460; (d) Reiter, M.; Torsell, S.; Lee, S.; MacMillan,
D., Chem. Sci. 2010, 1, 37-42; (e) Laplace, D.; Verbraeken, B.; Van Hecke, K.;
Winne, J., Chem. Eur. J. 2014, 20, 253-262; (f) Zhang, J.; Li, L.; Wang, Y.;
Wang, W.; Xue, J.; Li, Y., Org. Lett. 2012, 14 (17), 4518-4530; (g) Oblak, Z.;
162
VanHeyst, M.; Li, J.; Wiemer, A.; Wright, D., J. Am. Chem. Soc. 2014, 136,
4309-4315; (h) Hughes, C.; Trauner, D., Tetrahedron 2004, 60, 9675-9686; (i)
Garayalde, D.; Kruger, K.; Nevado, C., Angew. Chem. Int. Ed. Engl. 2011, 50,
911-915.
30.
McMills, M.; Wright, D., Synthetic Applications of 1,3-Dipolar Cycloaddition
Chemistry Toward Heterocycles and Natural Products. John Wiley & Sons:
Hoboken, 2003.
31.
Ye, T.; McKervey, M. A., Chem. Rev. 1994, 94, 1091-1160.
32.
Doyle, M. P.; Forbes, D. C., Chem. Rev. 1998, 911-936.
33.
(a) Padwa, A.; Chinn, G.; Hornbuckle, S.; Zhi, L., Tetrahedron Lett. 1989, 30,
301; (b) Dean, D.; Krumpe, K.; Padwa, A., J. Chem. Soc. Chem. Commun. 1989,
921; (c) Padwa, A.; Fryxell, G.; Zhi, L., J. Am. Chem. Soc. 1990, 112, 3100.
34.
Regitz, M., Angew. Chem. Int. Ed. Engl. 1967, 6, 733.
35.
Ibata, T.; Toyoda, J.; Sawada, M.; Tanaka, T., J. Chem. Soc. Chem. Commun.
1986, 1266.
36.
Padwa, A.; Precedo, L.; Semones, M., J. Org. Chem. 1999, 64, 4079.
37.
McMills, M.; Zhuang, L.; Wright, D.; Watt, W., Tetrahedron Lett. 1994, 35,
8311.
38.
Padwa, A.; Chinn, R.; Lin, Z., Tetrahedron Lett. 1989, 30, 1413.
39.
(a) Padwa, A.; Dean, D.; Zhi, L., J. Am. Chem. Soc. 1989, 111, 6451; (b)
Harwood, L. M.; Vickers, R. J., Synthetic Application of 1,3-Dipolar
163
Cycloaddition Chemistry Toward Heterocycles and Natural Products. John Wiley
& Sons: Hoboken, 2003.
40.
McMills, M.; Wright, D.; Zubkowski, J.; Valente, E., Tet. Lett. 1996, 37 (40),
7205-7208.
41.
Wright, D.; McMills, M., Org. Lett. 1999, 1 (4), 667-670.
42.
Ollero, L.; Castedo, L.; Dominguez, D., Tetrahedron 1999, 4445.
43.
Alonso, R.; Castedo, L.; Dominguez, D., Tet. Lett. 1986, 27 (30), 3539-3542.
44.
(a) Bentley, K., Nat. Prod. Rep. 2001, 18, 148-170; (b) Ollero, L.; Castedo, L.;
Dominguez, D., Tet. Lett. 1998, 39, 1413.
45.
(a) Mehta, G.; Muthusamy, S., Tetrahedron 2002, 58, 9477; (b) Muthusamy, S.;
Krishnamurthi, J., Top Heterocycl. Chem. 2008, 12, 147.
46.
(a) Garcia-Moreno, M. I.; Mellet, C.; Fernandez, J., Eur. J. Org. Chem. 2004,
1803; (b) Ostrowski, J.; Altenbach, H.; Wischnat, R.; Brauer, D., Eur. J. Org.
Chem. 2003, 1104; (c) Suau, R.; Najera, F.; Rico, R., Tetrahedron 1999, 55, 4019.
47.
Brown, H. C.; Campbell, J. B., J. Org. Chem. 1980, 45, 389-395.
48.
Valiulin, R. V.; Kutateladze, A. G., J. Org. Chem. 2008, 73 (16), 6393-6396.
49.
Marx, M.; Tidwell, T. T., J. Org. Chem. 1984, 49 (5), 788-793.
50.
Ahmed, A.; Dussault, P. H., Org. Lett. 2004, 6 (20), 3609-3611.
51.
Bow, W. F., Org. Lett. 2010, 12 (3), 440-443.
52.
Ramachary, D. B.; Narayana, V. V.; Ramakumar, K., Tet. Lett. 2008, 49 (17),
2704-2709.
164
53.
Liu, Y.; Yun, X.; Zhang-Negrerie, D.; Huang, J.; Du, Y.; Zhao, K., Synthesis
2011, 18, 2984-2994.
54.
Tan, J., Med. Chem. 2011, 7 (4), 309-316.
55.
Sammes, M. P., J. Chem. Soc. Perkin Trans. 1: Org. & Bioorg. Chem. 1981, 5,
1585-1590.
56.
Bertz, S.; Ogle, C.; Rastogi, A., J. Am. Chem. Soc. 2005, 127 (5), 1372-1373.
57.
Brown, H. C.; Subba Rao, B., J. Am. Chem. Soc. 1958, 80 (20), 5377-5380.
58.
Erhunmwunse, M.; Steel, P., J. Org. Chem. 2008, 73 (21), 8675-8677.
59.
DiLauro, A. M.; Seo, W.; Phillips, S. T., J. Org. Chem. 2001, 76, 7352-7358.
60.
Bendiabdellah, Y., Synthesis 2011, 14, 2321-2333.
61.
Chapelo, C. B.; Finch, M. A.; Lee, T. V.; Roberts, S. M.; Newtion, R. F., J. Chem.
Soc. Perkin Trans. 1 1980, 2084-2087.
62.
Haywood, J.; Morey, J. V.; Wheatley, A. E. H., Organometallics 2009, 28 (1), 3841.
63.
Hatcher, J. M.; Coltart, D. M., J. Am. Chem. Soc. 2010, 132 (13), 4546-4547.
64.
Beck, J. F., Eur. J. Inor. Chem. 2010, 32, 5146-5155.
65.
Clayden, J.; Stimson, C.; Keenan, M., Chem. Commun. 2006, 1393-1394.
66.
Manzel, K.; Dimichele, L.; Mills, P.; Frantz, D. E.; Nelson, T. D.; Kress, M. H.,
Synlett 2006, 1948-1952.
67.
Corey, E. J.; Kim, C. U., J. Am. Chem. Soc. 1972, 94, 7586-7587.
68.
Corey, E. J.; Suggs, J. W., Tet. Lett. 1975, 16, 2647-2650.
165
69.
(a) Krow, G. R.; Sonnet, P. E., Tetrahedron 2008, 64 (30-31), 7131-7135; (b)
Black, M.; Woodford, C.; Mills, N. S., J. Org. Chem. 2011, 76 (7), 2286-2290; (c)
Cooper, O. J.; Wooles, A. J.; McMaster, J.; Lewis, W.; Blake, A.; Liddle, S. T.,
Angew. Chem. Int. Ed. Engl. 2010, 49 (32), 5570-5573.
70.
Mehta, G.; Likhite, N. S., Tet. Lett. 2008, 49, 7113-7116.
71.
Treibs, W.; Orttmann, H., Chem. Ber. 1960, 93 (2), 545-551.
72.
Pietruszka, J.; Simon, R.; Kruska, F.; Braun, M., Eur. J. Org. Chem. 2009, 35,
6217-6224.
73.
Zielinski, T.; Kedziorek, M.; Jurczak, J., Chem. Eur. J. 2008, 14, 838-846.
74.
Moumne, R.; Lavielle, S.; Karoyan, P., J. Org. Chem. 2006, 71, 3332-3334.
75.
Saturnino, C.; Petrosino, S.; Ligresti, A.; Palladino, C.; De Martino, G.; Bisogno,
T.; Di Marzo, V., Bioorg. Med. Chem. Lett. 2010, 20, 1210-1213.
76.
Rosini, G.; Confalonieri, G.; Marotta, E.; Rama, F.; Righi, P., Org. Synth. 1997,
74 (158), 275.
77.
Baughman, T.; Sworen, J.; Wagener, K., Tetrahedron 2004, 60, 10943-10948.
78.
Sarel, S.; Newman, M., J. Am. Chem. Soc. 1956, 78 (20), 5416-5420.
79.
Heasley, V. L.; Shellhamer, D. F.; Carter, T. L.; Gipe, D. E.; Gipe, R. K.; Green,
R. C.; Hordeen, J.; Rempel, T. D.; Spaite, D. H., Tet. Lett. 1981, 22 (26), 24672470.
80.
Primerano, P.; Cordaro, M.; Scala, A., Tet. Lett. 2013, 54, 4061-4063.
81.
Okabayashi, T.; Iida, A.; Takai, K.; Nawate, Y.; Misaki, T., J. Org. Chem. 2007,
72, 8142-8145.
166
82.
Shao, L.; Shi, M., Synlett 2006, 1269-1271.
83.
Martinez-Solorio, D.; Jennings, M., Org. Lett. 2009, 11 (1), 189-192.
84.
Bartoszewicz, A.; Kalek, M.; Nilsson, J.; Hiresova, R.; Stawinski, J., Synlett
2008, 37-40.
85.
Bansal, R., Synthesis via Enolate Anions. In Synthetic Approaches in Organic
Chemistry, Hyde, C. W., Ed. Jones and Bartlett Pubishers, Inc: Narosa Publishing
House, 1996.
86.
(a) Suero, M., Chem. Eur. J. 2012, 18 (23), 7287-7295; (b) Arai, T., J. Org.
Chem. 1989, 54 (2), 414-420.
87.
Reetz, M. T.; Maier, W. F., Angew. Chem. Int. Ed. Engl. 1978, 17 (1), 48-49.
88.
Padwa, A.; Sa, M.; Weingarten, M., Tetrahedron 1997, 53 (7), 2371-2386.
89.
Harding, K.; May, L.; Dick, K., J. Org. Chem. 1975, 40, 1664-1665.
90.
Neises, B.; Steglich, W., Angew. Chem. Int. Ed. Engl. 1978, 17, 522-524.
91.
Mitsunobu, O., Synthesis 1981, 1, 1-28.
92.
Corey, E. J.; Masaji, O.; Vatakencherry, P., J. Am. Chem. Soc. 1961, 83 (5), 12511253.
93.
Druzgala, P.; Rosa, S.; Milner, P. Enantiomeric Compounds For Treatment of
Cardiac Arrhythmias and Methods of Use. 2002.
94.
Carmack, M. J., Heterocycl. Chem. 1989, 26, 1319.
95.
Nichols, A.; Zhang, P.; Martin, S., Tetrahedron 2012, 68, 7591-7597.
96.
Gabriele, B.; Mancuso, R.; Salerno, G.; Plastina, P., J. Org. Chem. 2008, 73 (2),
756-759.
167
97.
(a) Aponick, A.; Li, C.; Biannic, B., Org. Lett. 2008, 10 (4), 669-671; (b)
Davoust, M.; Briere, J.; Jaffres, P.; Metzner, P., J. Org. Chem. 2005, 70, 41664169.
98.
(a) Oishi, T., Org. Lett. 2008, 10 (22), 5203-5206; (b) Shaabania, A.; Mirzaeia, P.;
Naderia, S.; Leeb, D., Tetrahedron 2004, 60, 11415-11420; (c) Meyer, S.;
Schreiber, S., J. Org. Chem. 1994, 59, 7549-7552.
99.
Flick, A.; Caballero, M.; Padwa, A., Tetrahedron 2010, 66, 3643-3650.
100.
Oh, C.; Lee, S.; Hong, C., Org. Lett. 2010, 12 (6), 1308-1311.
101.
Roy, C.; Brown, H. C., J. Organometallic Chem. 2007, 692 (7), 1608-1613.
102.
Berliner, M.; Belecki, K., Org. Synth. 2007, 84 (102).
103.
Bailey, W.; Luderer, M.; Jordan, K., J. Org. Chem. 2006, 71 (7), 2825-2828.
104.
Huo, S., Org. Lett. 2003, 5 (4), 423-425.
105.
Srinivas, V.; Koketsu, M., J. Org. Chem. 2013, 78 (22), 11612-11617.
106.
Ciganek, E., Synthesis 1995, 10, 1311-1314.
107.
Davies, H.; Doan, B., J. Org. Chem. 1998, 63, 657-660.
108.
Ghosh, A.; Ghosh, M.; Niu, C.; Malouin, F.; Moellmann, U.; Miller, M.,
Chemistry & Biology 3 1996, 1011.
109.
Pramanik, A.; Stroeher, U.; Krejci, J.; Standish, A.; Bohn, E.; Paton, J.;
Autenrieth, I.; Braun, V., Int. J. Med. Microbiol. 2007, 297 (6), 459-469.
110.
Pearson, M.; Plantier-Royon, R.; Szymoniak, J.; Bertus, P.; Behr, J., Synthesis
2007, 22, 3589.
168
111.
(a) Rao, A. V.; Venkatswamy, S. M.; Deshpande, J. V.; Rao, B. R., J. Org. Chem.
1983, 48, 1552; (b) Corey, E. J.; Erickson, B. W., J. Org. Chem. 1971, 36, 3553.
112.
Stutz, P.; Stadler, P. A., Organic Syntheses 1988, 6, 109.
113.
Khan, A. T.; Mondal, E.; Sahu, P., Synlett 2003, 3, 377.
114.
Burghardt, T. E., J. Sulfur Chem. 2005, 26, 411-427.
115.
(a) Liu, K., J. Org. Chem. 2003, 68 (24), 9528-9531; (b) Van Brabandt, W.;
Vanwalleghem, M.; D'hooghe, M.; De Kimpe, N., J. Org. Chem. 2006, 71, 70837086.
116.
(a) Casiraghi, G.; Rassu, G.; Spanu, P.; Pinna, L., J. Org. Chem. 1992, 57, 3760;
(b) Hunt, J.; Laurent, P.; Moody, C., J. Chem. Soc. Perkin Trans. 1 2002, 2387.
117.
Wentrup, C.; Bibas, H.; Kuhn, A.; Mitschke, U.; McMills, M., J. Org. Chem.
2013, 78 (21), 10705-10717.
118.
Blankley, C.; Sauter, F.; House, H., Org. Synth. 1969, 49 (22), 258.
119.
Doyle, M. P.; Kalinin, A., J. Org. Chem. 1996, 61, 2179-2184.
120.
Ouihia, A.; Rene, L.; Guilhem, J.; Pascard, C.; Badet, B., J. Org. Chem. 1993, 58
(7), 1641-1642.
121.
Cainelli, G., Tet. Lett. 2003, 44 (33), 6269-6272.
122.
Qi, X.; Ready, J., Angew. Chem. Int. Ed. Engl. 2007, 46 (18), 3242-3244.
123.
Kazemi, F., Tetrahedron 2007, 63 (23), 5083-5087.
124.
Ziegler, F. E.; Fowler, K. W., J. Org. Chem. 1976, 41 (9), 1564-1566.
169
APPENDIX
SELECTED NMR SPECTRA
170
Normalized Intensity
0.40
0.35
0.30
0.25
0.20
7
6
12
5
H3C
4
10
O
3
11
13
2
1
9
CH3
O
3-(pent-4-en-1-yl)pentane-2,4-dione.1r.esp
8
H2C
14
12
11
10
9
8
M02(m)
M01(m)
1.00 2.07
7
6
5
Chemical Shift (ppm)
M03(m)
4
0.75
3
M05(m)
M07(m)
M06(m)
M04(s)
2.19
2
1
3.81 1.89 1.73 2.72
1.88
1.86
1.83
1.38
1.35
1.33
1.27
0.15
15
3.63
3.61
3.66
0.10
0.05
0
16
5.83
5.79
5.77
5.07
5.06
5.01
4.98
0
-1
-2
-3
-4
171
Normalized Intensity
0.11
0.10
0.09
0.08
0.07
0.06
0.05
2
3
12
5
H3C
4
14
8
6
O
9
7
13
10
11
O
13
CH3
12
3-(5-hydroxypentyl)pentane-2,4-dione.1r.esp
1
HO
15
11
10
9
8
M05(m)
0.08
M01(m)
4
1.00
7
6
5
Chemical Shift (ppm)
3
M02(s)
M04(m)
M03(br. s.)
2
1
0.42 0.58 0.66
1.35
0.04
0.03
0.02
0.01
0
16
2.10
0
-1
-2
-3
-4
172
Normalized Intensity
1.00
0.95
0.90
0.85
0.80
0.75
0.70
0.65
0.60
0.55
0.50
0.45
0.40
0.35
0.30
0.25
0.20
0.15
1
O
2
N
3
14
4
5
14
6
H3C
8
10
O
13
7
9
12
12
15
CH3
13
O
(E)-6-acetyl-7-oxooctanal O-methyl oxime.1r.esp
11
H3C
15
11
10
9
8
M01(s)
1.00
4
0.55
M02(m)
7
6
5
Chemical Shift (ppm)
3
M04(s)
M03(s)
2.46
2
5.84 3.75
2.25
0.10
0
0.05
16
6.88
1
0
-1
-2
-3
-4
173
Normalized Intensity
0.19
0.18
0.17
0.16
0.15
0.14
0.13
0.12
0.11
0.10
0.09
0.08
0.07
0.06
0.05
0.04
0.03
0.02
0.01
0
5
1
O
4
15
2
O
6
3
15
8
H3C
7
14
11
9
O
12
10
13
13
14
O
16
CH3
12
11
3-(4-(1,3-dioxolan-2-yl)butyl)pentane-2,4-dione.1r.esp
16
10
9
8
M01(m)
5.18
M02(m)
4
1.00
7
6
5
Chemical Shift (ppm)
3
M03(s)
2
17.85
2.10
1
0
-1
-2
-3
-4
174
Normalized Intensity
1.00
0.95
0.90
0.85
0.80
0.75
0.70
0.65
0.60
7
6
5
4
14
3
O
10
H3C
2
Si
1
13
H3C
9
14
12
12
CH3
CH3
CH3
11
13
11
((5-bromopentyl)oxy)(tert-butyl)dimethylsilane.1r.esp
Br
8
15
10
9
8
7
6
5
Chemical Shift (ppm)
M01(m)
M02(td)
3
2.00 1.81
4
M05(m)
M06(m)
M04(m)
M03(m)
1
2.19 4.67 1.35
2
0
0.87
0.05
0.55
0.50
0.45
0.40
0.35
0.30
0.25
0.20
0.15
0.10
0.05
0
16
3.62
0.87
1.50
1.49
1.48
1.46
1.58
3.38
3.34 3.37
1.88 3.35
1.86
1.83
-1
-2
-3
-4
175
Normalized Intensity
1.00
0.95
0.90
0.85
0.80
0.75
0.70
0.65
0.60
0.55
13
12
11
9
O
8
17
O
S
2
16
1
4
O
5
13
6
7
12
15
CH3
3
5-bromopentyl 4-methylbenzenesulfonate.1r.esp
14
Br
10
14
11
10
9
M01(d)
M02(m)
7
6
5
Chemical Shift (ppm)
2.00 2.08
8
M04(m)
M03(t)
4
3
M05(s)
M06(m)
M08(m)
M07(m)
2
1
2.08 1.72 2.74 1.56 2.52 2.43
3.95
0.50
15
3.97
3.99
0.45
0.40
0.35
0.30
0.25
0.20
0.15
0.10
0.05
0
16
1.40
1.35 1.38
1.37
2.38
1.74
1.76 1.63 1.61
1.59
1.78
3.28
3.30
3.25
3.23
7.29
7.27
7.22
7.71
7.74
0
-1
-2
-3
-4
176
Normalized Intensity
1.00
0.95
0.90
0.85
0.80
0.75
0.70
0.65
0.60
0.55
0.50
13
12
7
14
17
6
9
15
16
5
4
1
O
3
O
2
10
1-(benzo[d][1,3]dioxol-5-yl)-N-cyclohexylmethanimine.1r.esp
N
11
10
8
11
9
M01(s)
M02(d)
M03(d)
M10(s)
7.27
0.45
12
M04(s)
5.90
8
7
6
5
Chemical Shift (ppm)
1.00 1.01 1.01 0.99 1.99
6.71
0.40
13
6.74
7.00
0.35
14
4
M05(m)
M09(m)
M07(m)
M08(m)
M06(m)
1.61
3
1.01
2
1
2.01 2.95 1.88 3.08
3.07
3.05
3.03
3.02
1.77
1.72
1.50
1.46
1.19
1.26
1.15
1.22
0.30
0.25
0.20
15
3.11
3.10
3.08
0.15
0.10
0.05
0
16
8.11
0
-1
-2
-3
-4
177
Normalized Intensity
1.00
0.95
0.90
0.85
0.80
0.75
O
15
7
10
6
9
O
11
5
4
12
2
CH3
1
O
3
O
13
12
11
methyl 5-formylbenzo[d][1,3]dioxole-4-carboxylate.1r.esp
O
14
13
8
14
M01(s)
1.00
10
9
8
M05(s)
M04(d)
7.19
M02(s)
2.35
6.01
7
6
5
Chemical Shift (ppm)
1.17 1.66
7.36
7.33
0.70
15
M03(s)
4
1.47
3.87
0.65
0.60
0.55
0.50
0.45
0.40
0.35
0.30
0.25
0.20
0.15
0.10
0.05
0
16
9.75
3
2
1
0
-1
-2
-3
-4
178
Normalized Intensity
1.00
0.95
0.90
0.85
0.80
0.75
0.70
6
9
5
4
1
3
12
O
2
10
13
11
OH
1H-indene-3-carboxylic acid.1r.esp
8
7
14
12
11
10
9
M04(d)
M03(s)
M05(m)
M02(d)M06(d)
7
6
5
Chemical Shift (ppm)
1.06 1.13 1.17 1.30 1.02
8
M01(s)
4
2.00
3.62
0.65
0.60
0.55
0.50
0.45
0.40
0.35
15
7.66
7.52
7.41
7.32
0.30
0.25
0.20
0.15
0.10
0.05
0
16
8.12
8.10
3
2
1
0
-1
-2
-3
-4
179
Normalized Intensity
4
O
16
3
1
10
2
O
11
12
14
15
O
13
17
CH3
3-oxobutyl 1H-indene-3-carboxylate.1r.esp
5
9
8
6
7
12
11
10
9
M05(m)
M06(m)
M07(br. s.)
M03(d)
7
6
5
Chemical Shift (ppm)
1.00 2.39 1.56 0.56
8
M01(t)
M04(s)
M02(t)
2
2.13 2.85
3
2.00
4
2.17
0.45
0.40
0.35
0.30
13
2.85
2.87
2.83
4.52
4.54
4.50
0.25
14
7.40
0.20
15
7.38
7.29
7.26
7.22
0.15
0.10
0.05
0
16
7.94
7.91
1
0
-1
-2
-3
-4
180
Normalized Intensity
0.40
0.35
0.30
7
H3C
14
5
3-oxobutanoic acid.1r.esp
15
O
6
4
2
3
O
1
OH
13
12
11
10
9
8
7
6
5
Chemical Shift (ppm)
4
M01(s)
2.00
3
M02(s)
2
3.20
2.26
0.25
0.20
0.15
0.10
0.05
0
16
3.49
1
0
-1
-2
-3
-4
181
Normalized Intensity
5
6
O
4
3
O
12
Si
1
H3C
8
H3C
2
9
7
13
10
CH3
CH3
CH3
13
12
4-((tert-butyldimethylsilyl)oxy)butan-2-one.1r.esp
H3C
11
14
11
10
9
8
7
6
5
Chemical Shift (ppm)
M01(t)
M03(s)
M02(t)
2
2.013.00
3
2.00
4
M04(s)
8.78
0.83
1
M05(s)
0
5.69
0.00
0.85
0.80
0.75
0.70
0.65
0.60
0.55
15
2.12
0.50
0.45
0.40
0.35
0.30
0.25
0.20
0.15
0.10
0.05
0
16
2.56
2.58
2.54
3.83
3.86
3.81
-1
-2
-3
-4
182
Normalized Intensity
0.85
0.80
2
1
O
4
13
O
5
6
+
N
16
HN
14
+
8
Hg
7
N
15
9
O
17
O
10
13
11
12
12
CH3
bis(1-diazo-2-ethoxy-2-oxoethyl)mercury.1r.esp
H3C
3
14
HN
15
11
10
9
8
7
6
5
Chemical Shift (ppm)
M01(q)
4.00
4
3
2
M02(t)
1
6.94
1.28
1.30
1.33
0.75
0.70
0.65
0.60
0.55
0.50
0.45
0.40
0.35
0.30
0.25
0.20
0.15
0.10
0.05
0
16
4.26
4.23
4.28
4.21
0
-1
-2
-3
-4
183
Normalized Intensity
0.85
0.80
0.75
0.70
0.65
0.60
0.55
0.50
0.45
0.40
0.35
0.30
0.25
0.20
0.15
0.10
0.05
0
3
H3C
15
2
O
1
10
HN
14
4
9
5
O
6
+
N
7
12
11
8
O
Br
13
12
ethyl 4-bromo-2-diazo-3-oxobutanoate.1r.esp
16
11
10
9
8
7
6
5
Chemical Shift (ppm)
M01(q)
M02(s)
2.00 4.57
4
3
2
M03(t)
1.25
1
3.18
1.27
1.23
3.89
4.14
4.11
4.16
0
-1
-2
-3
-4
184
Normalized Intensity
1.00
0.95
0.90
0.85
0.80
0.75
0.70
0.65
0.60
0.55
0.50
0.45
18
13
12
14
11
O
10
9
8
S
7
4
N
5
3
6
2
1
O
11
2-(benzofuran-2-yl)-1-morpholinoethane-1-thione.1r.esp
17
16
15
12
10
9
M04(m)
M01(s)
M03(d)
M02(d)
M06(m)
M05(s)
M08(m)
M07(m)
4
M09(m)
3
2.39 2.31 3.01 2.76 2.12
7
6
5
Chemical Shift (ppm)
1.38 1.40 1.65 1.00
8
3.80
0.40
13
6.67
4.49
4.39
3.91
3.82
4.38
0.35
14
2.94
2.92
2.91
0.30
0.25
0.20
15
7.26
7.23
7.21
0.15
0.10
0.05
0
16
7.55
7.53
2
1
0
-1
-2
-3
-4
185
Normalized Intensity
0.075
0.070
0.065
0.060
0.055
0.050
0.045
0.040
0.035
0.030
0.025
0.020
0.015
0.010
0.005
0
8
7
9
6
15
4
5
3
O
1
14
2
13
O
10
13
11
2-(benzofuran-2-yl)acetic acid.1r.esp
16
12
OH
12
11
10
9
M05(m)
M06(m)
M04(m)
M03(m)
M02(m)
7
6
5
Chemical Shift (ppm)
3.69 2.39 2.60 2.68 1.05
8
M01(m)
2.00
4
3
2
1
0
-1
-2
-3
-4
186
Normalized Intensity
1.0
0.9
0.8
0.7
9
4
5
3
1
O
2
10
14
O
12
O
13
11
13
CH3
methyl 2-(benzofuran-2-yl)acetate.1r.esp
8
7
6
14
12
11
10
9
M04(m)
M01(s)
M03(d)
M02(d)
7
6
5
Chemical Shift (ppm)
1.301.31 2.84 1.00
8
M05(s)
M06(s)
3.67
4
3
3.19 1.55
3.33
0.6
0.5
0.4
0.3
15
6.79
7.51
7.25
7.22
7.20
0.2
0.1
0
16
7.61
7.58
2
1
0
-1
-2
-3
-4
187
Normalized Intensity
1.00
0.95
0.90
0.85
0.80
0.75
0.70
0.65
0.60
0.55
0.50
0.45
0.40
0.35
0.30
0.25
0.20
9
8
OH
7
OH
10
13
11
CH
2-(1-hydroxyprop-2-yn-1-yl)phenol.1r.esp
2
3
4
1
6
14
5
15
12
11
10
9
M05(s)
M06(m)
M03(m)
M04(m)
M02(m)
7
6
5
Chemical Shift (ppm)
2.063.00 3.31 5.76 1.61
8
M01(s)
4
1.00
3.61
0.15
0.10
0.05
0
16
6.94
3
2
1
0
-1
-2
-3
-4
188
Normalized Intensity
1.00
0.95
0.90
0.85
6
4
3
O
Si
1
12
13
12
CH3
CH3
11
CH3 CH3
10
13
9
(4-bromobutoxy)(tert-butyl)dimethylsilane.1r.esp
7
Br
5
2
8
H3C
14
11
10
9
8
7
6
5
Chemical Shift (ppm)
M04(m)
M03(t)
3
1.27 2.18
4
M02(s)
M06(m)
M05(m)
0.82
1
1.35 1.57 9.25
2
M01(s)
0
6.00
0.00
0.80
0.75
0.70
0.65
0.60
0.55
0.50
0.45
0.40
0.35
0.30
0.25
0.20
15
1.58
1.57
1.55
1.53
0.15
0.10
0.05
0
16
3.57
3.55
3.53
3.47
3.44
3.42
3.35
-1
-2
-3
-4
189
Normalized Intensity
1.00
0.95
0.90
0.85
0.80
0.75
0.70
0.65
0.60
0.55
0.50
0.45
0.40
O
4
1
3
2
7
OH
tetrahydro-2H-pyran-2-ol.1r.esp
6
5
13
12
11
10
9
8
M01(s)
1.00
7
6
5
Chemical Shift (ppm)
M04(ddd)
M03(m)
1.74
3.16
4
3
1.71 1.73
2
10.55
1.70
0.35
14
3.90
3.89
3.88
0.30
0.25
0.20
15
1.89
3.87
3.86
3.85
3.83
1.88
1.87
1.85
1.84
1.93
0.15
0.10
0.05
0
16
5.30
1
0
-1
-2
-3
-4
190
Normalized Intensity
HO
7
6
5
4
0.85 hept-6-ene-1,5-diol.1r.esp
0.80
0.75
0.70
0.65
0.60
0.55
0.50
0.45
3
2
1
OH
8
9
CH2
12
11
10
9
8
M02(m)
M01(dd)
1.00 2.54
7
6
5
Chemical Shift (ppm)
M03(m)
M04(m)
4.47 7.39
4
3
M05(m)
1.56
1.61
1.59
2
25.58
1.68
1.66 1.63
0.40
0.35
0.30
13
3.49
3.47
3.45
4.08
4.00 4.02 4.05
0.25
14
5.60
5.57
5.54
0.20
15
4.11
4.13
0.15
0.10
0.05
0
16
5.85
5.81
5.66
5.63
1
0
-1
-2
-3
-4
191
Normalized Intensity
0.30
0.25
0.20
0.15
0.10
0.05
0
1
Si
H3C
15
16
H3C
9
H3C
H3C
10
15
CH3
12
11
3
4
O
2
14
5
6
7
13
8
OH
13
14
12
CH2
7-((tert-butyldimethylsilyl)oxy)hept-1-en-3-ol.1r.esp
16
11
10
9
8
M02(m)
M01(m)
1.00 4.23
7
6
5
Chemical Shift (ppm)
4
M06(m)
13.03
3
0.06
1
0
39.44 90.32 58.88
0.88
M04(s) M03(s)
M05(m)
2
3.49
3.47
3.45
1.66
1.63
1.61
1.58
1.56
-1
-2
-3
-4
192
Normalized Intensity
0.25
0.20
5
3
6
2
1
15
18
7
Si
22
20
17
9
19
O
8
CH3
25
21
10
11
12
13
13
14
OH
23
24
12
CH2
7-((tert-butyldiphenylsilyl)oxy)hept-1-en-3-ol.1r.esp
4
16
H3C
H3C
26
14
11
10
9
M08(m)
M07(dd)
7.28
7.26
8
M02(m)
M01(m)
1.00 2.39
7
6
5
Chemical Shift (ppm)
40.98 60.94
7.24
0.15
15
3
M04(m)
M03(m)
3.44 8.88
4
1
26.31 95.78
0.95
M05(s)
M06(m)
2
1.54
1.52
1.49
0.10
0.05
0
16
7.61
7.61
7.59
0
-1
-2
-3
-4
193
Normalized Intensity
0.85
0.80
0.75
0.70
0.65
0.60
0.55
0.50
0.45
0.40
0.35
0.30
0.25
0.20
10
9
8
7
14
5
3
H3C
6
O
2
N
1
O
13
4
CH3
12
5-hydroxy-N-methoxy-N-methylpentanamide.1r.esp
HO
11
15
11
10
9
8
7
6
5
Chemical Shift (ppm)
M01(s)
M03(t)
4
3
2
2.86 2.13 3.00 2.03 2.66 2.40
3.18
M02(s)
M06(m)
M05(m)
M04(t)
1.77
1.79
0.15
0.10
0.05
0
16
1
1.74
1.72
1.64
1.59 1.61
1.57
2.47
2.49
2.45
3.68
3.64
3.62
0
-1
-2
-3
-4
194
Normalized Intensity
1.00
0.95
0.90
0.85
0.80
0.75
0.70
6
3
1
2
7
Br
8
9
2-(2-bromophenyl)ethan-1-ol.esp
5
4
14
10
OH
13
12
11
10
9
M01(t)
3.91
3.89
4
2.15
3.93
M04(d)
M06(m)
M05(m)
7
6
5
Chemical Shift (ppm)
1.02 2.28 1.00
8
M02(t)
3.06
3
2.12
3.08
0.65
0.60
0.55
0.50
15
1.05
1
M03(br. s.)
2
1.55
0.45
0.40
0.35
0.30
0.25
0.20
0.15
0.10
0.05
0
16
7.28
7.12
7.10
7.09
3.03
7.30
7.59
7.56
0
-1
-2
-3
-4
195
Normalized Intensity
1.00
0.95
0.90
6
3
1
2
7
Br
8
9
13
O
H3C
14
16
CH3
17 CH
3
15
CH3
CH3
11
Si
12
(2-bromophenethoxy)(tert-butyl)dimethylsilane.esp
5
4
10
12
11
10
9
M03(m)
M02(m)
M01(d)
7
6
5
Chemical Shift (ppm)
0.82 2.53 0.84
8
M04(m)
M05(t)
1.72
3
1.99
4
2
M06(s)
M07(s)
TMS
9.20
0
6.00
0.89
1
0.00
0.85
0.80
0.75
0.70
0.65
0.60
0.55
0.50
0.45
0.40
13
3.02
3.00
2.98
0.35
14
3.83
0.30
15
3.85
3.88
0.25
0.20
0.15
0.10
0.05
0
16
7.56
7.53
7.27
7.30
7.27
7.24
7.21
7.11
7.08
-1
-2
-3
-4
196
Normalized Intensity
3
2
5
6
7
8
9
13
10
CH2
12
11
10
9
8
1.91
M03(m)
M05(m)
M04(m)
M06(m)
M07(m)
M09(m)
M08(br. s.)
2.07
M02(m)
M01(ddt)
0.94
7
6
5
Chemical Shift (ppm)
4
3
2
1
1.170.83 0.83 1.00 2.00 1.67 3.61
2.21
1-bromooct-7-en-2-ol.esp
4
Br
HO
14
1.56
1.0
0.9
1
15
3.40
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
16
3.78
1.58
2.05
3.54
3.42
3.39
3.36
4.98
5.04
4.94
1.45
1.42
1.37 1.38
1.33
1.31
5.76
5.74
3.80
3.81
3.85
3.84 3.82
5.82
5.80
5.85
5.88
0
-1
-2
-3
-4
197
Normalized Intensity
1.0
0.9
0.8
0.7
0.6
0.5
0.4
O
6
Br
2
5
3
O
4
14
8
9
10
13
11
12
13
12
CH2
8-bromo-7-(methoxymethoxy)oct-1-ene.esp
H3C
7
1
15
11
10
9
8
M05(m)
M07(m)
M06(m)
M04(m)
M03(m)
M02(m)
M01(m)
7
6
5
Chemical Shift (ppm)
4
3
0.30 0.63 1.29 0.90 1.09 1.73 3.50
2.06
2.04
3.34
3.39
3.50
3.52
M09(m)
M10(br. s.)
M08(d)
1.35
2
1
0.60 2.73 4.00
1.62
1.60
1.58
1.55
0.3
0.2
0.1
0
16
4.59
3.76
3.75
3.67
4.70
4.67
5.82
5.79
5.77
5.73
5.01
4.95
0
-1
-2
-3
-4
198
Normalized Intensity
0.70
0.65
0.60
0.55
0.50
0.45
0.40
3
6
2
1
O
14
13
H
13a
8
9
O
15
10
11
O
12
CH3
12
methyl (E)-3-(2-formylphenoxy)acrylate.esp
4
5
7
O
13
11
0.25
0.20
0.15
0.10
0.05
0
10
0.71
M01(s)
14
M06(d)
M05(t)
M04(m)
8
M07(d)
0.83
7
6
5
Chemical Shift (ppm)
0.78 0.75 0.90 0.87 0.83
9
M08(m)
4
3.00
3.79
3.77
3.74
0.35
15
5.69
5.65
0.30
16
7.62
7.96
7.96
7.89
7.94
7.85
7.67
7.34
7.19
7.16
10.39
3
2
1
0
-1
-2
-3
-4
199
Normalized Intensity
0.55
0.50
0.45
0.40
0.35
9
4
5
3
1
14
2
O
O
10
15
O
11
12
O
13
CH3
methyl 2-(3-oxo-2,3-dihydrobenzofuran-2-yl)acetate.esp
8
7
6
11
10
9
0.05
0
M02(m)
M01(m)
8
1.65 1.94
M03(dd)
0.71
7
6
5
Chemical Shift (ppm)
M05(dd)
M06(dd)
M04(m)
4
3
3.00 0.91 0.81
3.66
3.65
2
3.05
3.04
3.00
2.72 2.99
2.78
2.75
2.69
0.30
12
4.85
4.84
4.82
4.81
0.25
13
7.01
0.20
14
0.15
15
0.10
16
7.63
7.61
7.55
7.08
7.04
7.53
1
0
-1
-2
-3
-4
200
Normalized Intensity
0.55
0.50
0.45
0.40
0.35
O
CH3
19
16
15
14
9
S
1
7
6
S
5
3
2
O
8
CH3
CH3 13
4
12
11
10
5-(1,3-dithian-2-yl)-2,2,2',2'-tetramethyl-4,4'-bi(1,3-dioxolane).1r.esp
O
20
H3C
17
18
11
O
10
12
13
9
8
7
6
5
Chemical Shift (ppm)
M07(m)
5.88
4
M02(s)
M03(s)
M01(s)
M04(s)
M08(br. s.)
M05(m)
M06(br. s.)
3
2
1
0
2.19 2.42 1.93 3.00 2.69 2.88 2.86
1.49
1.46
1.41
1.36
0.30
0.25
14
3.04
2.89
2.85
2.74
2.08
0.20
15
4.19
4.11
4.03
0.15
0.10
0.05
0
16
4.26
-1
-2
-3
-4
201
Normalized Intensity
18
12
CH3
2
9
HO
4
3
8
20
O
16
O
15
17
O H3C
12
11
10
9
8
methyl 2-hydroxy-2-(2,2,2',2'-tetramethyl-[4,4'-bi(1,3-dioxolan)]-5-yl)acetate.1r.esp
19
O
5
11
10
1
O
6
13
CH3
CH3 7
14
M08(m)
M06(m)
M05(s)
M07(d)
3.81
7
6
5
Chemical Shift (ppm)
4
3
1.02 1.00 4.15 3.00
4.20
4.10
4.05
H3C
13
14
O
15
2
M02(s)
M01(s)
M04(s)
M03(s)
1
3.00 2.97 2.77 2.97
1.40
1.37
1.34
1.32
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
16
4.34
4.31
0
-1
-2
-3
-4
202
Normalized Intensity
1.0
0.9
0.8
0.7
0.6
17
12
CH3
8
15
11
10
9
1-(2,2,2',2'-tetramethyl-[4,4'-bi(1,3-dioxolan)]-5-yl)ethane-1,2-diol.1r.esp
18
HO
9
O
11
10
16
OH
12
8
7
6
5
Chemical Shift (ppm)
M05(m)
M06(m)
5.53 1.92
4
3
M04(br. s.)
M01(s)
M03(s)
M02(s)
1.28
2
1
3.76 2.94 2.23 3.00
1.36
1.35
H3C
13
14
O
6
13
CH3
CH3 7
O
3
4
2
5
1
O
14
4.07
0.5
0.4
15
3.98
3.92
3.74 3.90
3.71
3.70
3.69
0.3
0.2
0.1
0
16
4.12
4.10
0
-1
-2
-3
-4
203
Normalized Intensity
0.16
0.15
0.14
0.13
0.12
0.11
0.10
0.09
0.08
0.07
0.06
0.05
0.04
0.03
0.02
0.01
0
18
13
14
O
H3C
15
17
12
CH3
O
5
11
10
1
O
14
2
6
9
HO
4
3
8
O
CH3
CH3 7
15
16
O
M07(m)
13
12
11
M06(m)
0.01
10
9
8
7
6
5
Chemical Shift (ppm)
M05(m)
M08(m)
5.39 2.25
4
3
2
M02(s)
M01(s)
M03(s)
M04(s)
1
2.38 3.20 2.56 3.00
1.36
1.35
1.32
1.28
2-hydroxy-2-(2,2,2',2'-tetramethyl-[4,4'-bi(1,3-dioxolan)]-5-yl)acetaldehyde.1r.esp
16
3.94
3.92
3.89
3.70
3.69
3.67
4.07
3.98
4.10
4.09
4.12
0
-1
-2
-3
-4
204
Normalized Intensity
1.00
0.95
0.90
0.85
0.80
0.75
5
4
H
N
1
3
2
1,5-dihydro-2H-pyrrol-2-one.1r.esp
6
O
12
11
10
9
0.50
0.45
0.40
0.35
0.30
0.25
0.20
0.15
0.10
0.05
0
M04(br. s.)
8
0.73 1.19
M01(d)
1.00
7
6
5
Chemical Shift (ppm)
M03(m)
4
3.71
3.65
2.07
3.61
0.70
0.65
13
M02(d)
14
6.18
0.60
15
6.13
0.55
16
7.13
7.18
7.35
3
2
1
0
-1
-2
-3
-4
205
Normalized Intensity
0.70
0.65
0.60
0.55
0.50
0.45
0.40
0.35
0.30
0.25
0.20
0.15
0.10
0.05
0
15
9
8
H3C
O
5
7
13
H3C
O
10
4
14
12
3
11
2
O
CH3
6
N
1
13
12
11
tert-butyl 2-oxo-2,5-dihydro-1H-pyrrole-1-carboxylate.1r.esp
16
10
9
8
M02(m)
0.75
7
6
5
Chemical Shift (ppm)
4
M01(m)
2.00
3
M03(s)
2
273.34
1.58
1
0
-1
-2
-3
-4
206
Normalized Intensity
0.40
0.35
8
14
13
O
CH3
6
5
11
10
9
tert-butyl 2-((tert-butyldimethylsilyl)oxy)-1H-pyrrole-1-carboxylate.1r.esp
9
H3C
O
7
15
H3C
4
12
M03(s)
M02(s)
M01(t)
8
1.00 1.02 0.93
7
6
5
Chemical Shift (ppm)
4
3
2
M04(s)
M06(s)
M05(s)
0.82
1
0
1.12 0.74 0.72
0.78
0.30
12
13
H3C
N
18
O 2 1
17
10
Si
11 CH3 3
CH3
16
20 CH3
19
H3C
14
0.00
0.25
15
7.09
7.06
0.20
0.15
0.10
0.05
0
16
7.64
7.67
7.61
-1
-2
-3
-4
207
Normalized Intensity
1.00
0.95
0.90
0.85
0.80
0.75
5
4
6
3
O
10
1
2
9
8
O
7
S
11
12
N
13
O
16
14
15
OH
M03(s)
M02(d)
M01(d)
NH
2-(2-tosylhydrazono)acetic acid.1r.esp
9
H3C
10
7
2.00 2.04 1.04
8
6
5
4
3
2
1
0
Chemical Shift (ppm)
M04(s)
3.15
2.44
0.70
0.65
0.60
0.55
0.50
0.45
0.40
0.35
0.30
0.25
0.20
0.15
0.10
0.05
0
11
7.84
7.81
7.45
7.32
-1
-2
-3
-4
-5
-6
-7
-8
-9
208
Normalized Intensity
1.00
0.95
0.90
0.85
0.80
0.75
0.70
0.65
0.60
9
2
O
5
1
N
10
O
O
6
14
8
7
O
13
+
11a
H
NH
N
12
11
13
12
2,5-dioxopyrrolidin-1-yl 2-diazoacetate.1r.esp
3
4
15
11
10
9
8
M01(br. s.)
1.00
7
6
5
Chemical Shift (ppm)
4
M02(m)
2.83
3
6.62
2.81
0.55
0.50
0.45
0.40
0.35
0.30
0.25
0.20
0.15
0.10
0.05
0
16
5.14
2
1
0
-1
-2
-3
-4
209
Normalized Intensity
19
H3C
17
16
18
15
O
11
13
14
10
S
O
8
NH N
12
9
7
6
O
5
4
1
N
3
2
11
10
9
M02(s)
M03(d)
M01(d)
0.70 N'-(2-(azetidin-1-yl)-2-oxoethylidene)-4-methylbenzenesulfonohydrazide.1r.esp
0.65
0.60
0.55
0.50
0.45
0.40
0.35
12
7
6
5
Chemical Shift (ppm)
2.00 1.75 0.63
8
M04(t)
M05(t)
1.49 2.65
4
3
M07(t)
M06(s)
2.44
2
2.51 2.06
2.36 2.38
0.30
13
4.13
4.10
0.25
14
4.35
4.33
0.20
15
7.34
7.31
6.74
0.15
0.10
0.05
0
16
7.85
7.82
1
0
-1
-2
-3
-4
210
Normalized Intensity
4
N
1
3
2
6
O
5
7
11
8
O
10
CH3
O
9
12
0.70 methyl 3-(azetidin-1-yl)-3-oxopropanoate.1r.esp
0.65
0.60
0.55
0.50
0.45
0.40
0.35
0.30
13
11
10
9
8
M04(m)
M03(t)
M02(s)
M01(s)
3.77
7
6
5
Chemical Shift (ppm)
4
3
2.03 2.77 3.00 1.95
4.10
0.25
14
3.22
0.20
15
M05(m)
2
2.03
2.34
2.32
2.29
0.15
0.10
0.05
0
16
4.25
4.22
1
0
-1
-2
-3
-4
211
Normalized Intensity
1.00
0.95
0.90
0.85
0.80
0.75
0.70
0.65
0.60
0.55
0.50
0.45
0.40
0.35
0.30
0.25
0.20
0.15
0.10
0
0.05
2
4
N
1
3
15
6
O
5
13
8
O
+
12
NH
11
N
7
14
10
CH3
9
O
13
12
11
methyl 3-(azetidin-1-yl)-2-diazo-3-oxopropanoate.1r.esp
16
10
9
8
7
6
5
Chemical Shift (ppm)
M02(m)
M03(s)
3.79
2.76 1.25
4
3
M01(t)
2
2.00
3.48
3.46
3.39
3.37
2.32
2.29
2.26
1
0
-1
-2
-3
-4
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